rs142773283

chr7-117603729-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Strong

The NM_000492.4(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 NM_000492.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:7
• Conservation: PhyloP100: 7.82

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 25) in uniprot entity CFTR_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000492.4
• 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=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2855T>C	p.Met952Thr	missense_variant	17/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2855T>C	p.Met952Thr	missense_variant	17/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152212 Hom.: 0 Cov.: 32

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: 67 AN: 251366 Hom.: 1 AF XY: 0.000280 AC XY: 38 AN XY: 135836

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.: 1 Cov.: 32 AF XY: 0.000404 AC XY: 294 AN XY: 727170

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: 25 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74352

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.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4 Uncertain:7

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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. -
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 -

not provided Pathogenic:1 Uncertain:3

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. -
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	Eurofins Ntd Llc (ga)	Oct 07, 2016	- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 09, 2023

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. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 255324 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (0.00027 vs 0.013), allowing no conclusion about variant significance. c.2855T>C has been reported in the literature in compound heterozygosity with a second pathogenic CFTR variant in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (e.g. Mak_1999, Casals_2000, Gilljam_2004, Wilschanski_2006). These data indicate that the variant may be associated with disease. The variant has also been reported in individuals with chronic pancreatitis (e.g. Keiles_2006, Schneider_2011) and cystic fibrosis (e.g. Mongodin_2002, Terlizzi_2020). The variant was also detected along with a deletion in CFTR in an individual affected with aquagenic palmoplantar keratoderma (Raynal_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants that affect this same amino acid residue have been classified internally as pathogenic (e.g. c.2856G>A, p.Met952Ile and c.2856G>C, p.Met952Ile), supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10875853, 17003641, 20977904, 10376575, 14551163, 16840743, 24451227, 25735457, 27026144, 25033378, 29589582, 26354092, 11796591, 31310009, 31682332, 32773111, 33322690, No_PMID, 34996830, 34782259). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely pathogenic (n=3) and VUS (n=6). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
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	D
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

Other links and lift over

dbSNP: rs142773283; hg19: chr7-117243783;