rs142773283

Positions:

chr7-117603729-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_ModeratePP5_Strong

The ENST00000003084.11(CFTR):c.2855T>C(p.Met952Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,613,954 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M952I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 1 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:4U:8

Conservation

PhyloP100: 7.82

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000003084.11

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117603730-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2768661.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 7-117603729-T-C is Pathogenic according to our data. Variant chr7-117603729-T-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 53579.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=8}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2855T>C	p.Met952Thr	missense_variant	17/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2855T>C	p.Met952Thr	missense_variant	17/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000267

AC:

AN:

251366

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000536

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000390

AC:

570

AN:

1461742

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

294

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000500

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000164

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000266

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4Uncertain:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:3Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 952 of the CFTR protein (p.Met952Thr). This variant is present in population databases (rs142773283, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with CFTR related disorder, chronic pancreatitis, congenital bilateral absence of the vas deferens, and/or elevated chlorine and sodium levels (PMID: 10875853, 17003641, 20977904, 25087612, 27026144, 29589582, 34949556). ClinVar contains an entry for this variant (Variation ID: 53579). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 34949556). This variant disrupts the p.Met952 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10200050, 15070876, 15287992, 16272798, 16980811, 21520337, 23276700). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, reviewed by expert panel	research	CFTR2	Dec 20, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, PM5, PP3, BS2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2018	The CFTR c.2855T>C (p.Met952Thr) missense variant has been reported in at least six studies and is reported in at least six individuals with CFTR-related disorders. Three of the individuals were males presenting with congenital bilateral absence of the vas deferens (CBAVD) in whom the p.Met952Thr variant was identified in a compound heterozygous state with the p.Phe508del variant (Mak et al. 1999; Casals et al. 2000; Wilschanski et al. 2006). In addition one individual with aquagenic palmoplantar keratoderma also carried the variant in a compound heterozygous state (Cabrol et al. 2016). The remaining two individuals presented with pancreatitis. In both individuals, the p.Met952Thr variant was identified in a heterozygous state along with additional variants in other genes including an intronic heterozygous variant in the PRSS1 gene and a homozygous variant in the SPINK1 gene (Keiles et al. 2006; Schneider et al. 2011). The p.Met952Thr variant was present in one of 274 controls (Wilschanski et al. 2006; Schneider et al. 2011; Martinez et al. 2014) and is also reported at a frequency of 0.00058 in the European (non-Finnish) population of the Exome Aggregation Consortium, including one individual with the variant in a homozygous state. This variant has not been reported in individuals presenting with classic CF and is thought to be associated with a mild CF phenotype when present in trans with a second pathogenic variant (Schneider et al. 2011). Another variant at the same amino acid position (p. Met952Ile) has also been identified in probands with CFTR-related disorders (Uzun et al. 2005; Steiner et al. 2011). Based on the collective evidence, the p.Met952Thr variant is classified as likely pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 16, 2023	The p.M952T variant (also known as c.2855T>C), located in coding exon 17 of the CFTR gene, results from a T to C substitution at nucleotide position 2855. The methionine at codon 952 is replaced by threonine, an amino acid with similar properties. This variant has been described in individuals with congenital bilateral absence of the vas deferens (CBAVD) who were also heterozygous for p.F508del; however, the phase of the variants was not confirmed (Mak V et al. JAMA, 1999 Jun;281:2217-24; Casals T et al. Hum. Reprod., 2000 Jul;15:1476-83). In addition, this variant was reported in trans with a multi-exon deletion in an individual with aquagenic palmar keratoderma and elevated sweat chloride levels (Cabrol C et al. Acta Derm. Venereol., 2016 08;96:848-9). This variant was also reported in a patient with familial chronic pancreatitis who was homozygous for a pathogenic SPINK1 vairant (Schneider A et al. Gastroenterology, 2011 Jan;140:162-71). This variant has also been described in control and general populations (Martinez B et al. J. Hum. Genet., 2014 Apr;59:206-10; Grangeia A et al. Pulmonology Mar;24:3-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2024	Variant summary: CFTR c.2855T>C (p.Met952Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 1613954 control chromosomes in the gnomAD database, including 1 homozygote with an XX sex chromosome complement. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00037 vs 0.013). c.2855T>C has been reported in the literature in mutiple individuals affected with CFTR-Related Diseases, including pancreatitis, congenital absence of the vas deferens, and cystic fibrosis (example, Mak_1999, Casals_2000, Medza_2021, Stahl_2019, Keiles_2006, Schneider_2011). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.2856G>A, p.Met952Ile), supporting the critical relevance of codon 952 to CFTR protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 21.27% of normal chloride channel conductance relative to wild type (example, Bihler_2024) however other laboratories have observed different results in other cell lines (example, Hatton_2022). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 27026144, 10875853, 14551163, 29589582, 34949556, 17003641, 25033378, 10376575, 26354092, 24451227, 33919435, 32773111, 11796591, 24697796, 25735457, 34782259, 31310009, 34996830, 20977904, 31682332, 30420236, 33322690, 16840743, No_PMID). ClinVar contains an entry for this variant (Variation ID: 53579). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 23, 2023	PP3, PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2023	The CFTR c.2855T>C; p.Met952Thr variant (rs142773283) is reported in the literature in multiple individuals affected with CFTR-related disorders when found with a pathogenic variant on the opposite chromosome (Cabrol 2016, Casals 2000, Gilljam 2004, Mak 1999, Wilschanski 2006). This variant is listed in ClinVar (Variation ID: 53579), and is observed in the general population with an overall allele frequency of 0.025% (71/282774 alleles, including a single homozygote) in the Genome Aggregation Database. The methionine at codon 952 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.924). Additionally, another variant at this codon (c.2856G>C; p.Met952Ile) has been reported in individuals with CFTR-related disorders (Steiner 2011, Uzun 2005). While the p.Met952Thr variant is unlikely to cause classic cystic fibrosis, it is considered likely pathogenic for CFTR-related disorders. References: Cabrol C et al. Aquagenic Palmoplantar Keratoderma as a CFTR-related Disorder. Acta Derm Venereol. 2016 Aug 23;96(6):848-9. PMID: 27026144. Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000; 15(7):1476-83. PMID: 10875853. Gilljam M et al. Airway inflammation and infection in congenital bilateral absence of the vas deferens. Am J Respir Crit Care Med. 2004; 169(2):174-9. PMID: 14551163. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999; 281(23):2217-24. PMID: 10376575. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. PMID: 21520337. Uzun S et al. Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens. Tohoku J Exp Med. 2005 Dec;207(4):279-85. PMID: 16272798. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006; 174(7):787-94. PMID: 16840743. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;.;.;D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.1

H;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.0

D;.;.;D;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

0.99

D;.;.;.;.

Vest4

0.96

MVP

1.0

MPC

0.014

ClinPred

0.90

GERP RS

4.7

Varity_R

0.91

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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