7-117548701-G-A

Position:

chr7-117548701-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000492.4(CFTR):c.1270G>A(p.Gly424Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,613,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 3.36

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:

CFTR-AS1 (HGNC:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13353205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1270G>A	p.Gly424Ser	missense_variant	10/27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.222-6162C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1270G>A	p.Gly424Ser	missense_variant	10/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000934

AC:

AN:

246210

Hom.:

AF XY:

0.0000749

AC XY:

AN XY:

133598

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000163

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.000207

AC:

303

AN:

1461124

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

136

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000264

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000118

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 19, 2019	This CFTR variant (rs371107552) is rare (<0.1%) in large population datasets1,2 (gnomAD: 24/277606 total alleles; 0.0087%, no homozygotes). Six submitters in ClinVar classify the clinical significance of this variant as uncertain. One study has demonstrated that CFTR c.1270G>A may decrease inclusion of exon 10 (legacy exon 9) during splicing; however, bioinformatics tools do not predict this variant will alter typical splicing patterns. Two bioinformatics tools predict this amino acid substitution will be tolerated. The glycine residue at this position is not well conserved across species assessed. Due to insufficient evidence, we consider the clinical significance of c.1270G>A uncertain at this time. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2024	The p.G424S variant (also known as c.1270G>A), located in coding exon 10 of the CFTR gene, results from a G to A substitution at nucleotide position 1270. The glycine at codon 424 is replaced by serine, an amino acid with similar properties. This alteration was reported in two related individuals with diffuse bronchiectasis and rheumatoid arthritis; one of the individuals also carried the p.G576A alteration but the phase was unclear (Puéchal X. et al., Ann. Rheum. Dis. 2011 Apr; 70(4):653-9). One study of Hep3B cells transfected with this alteration showed some mRNA transcripts with skipping of exon 9 in addition to wild type mRNA transcripts (Pagani F et al., J. Biol. Chem. 2003 Jul; 278(29):26580-8). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 04, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the CFTR protein (p.Gly424Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with rheumatoid arthritis and bronchiectasis (PMID: 21131649). ClinVar contains an entry for this variant (Variation ID: 286406). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 12732620). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 16, 2018	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2017	The CFTR c.1270G>A; p.Gly424Ser variant (rs371107552) has been reported in two individuals from a family with rheumatoid arthritis and bronchiectasis (Puechal 2011), and reported to cause exon 9 skipping in a portion of transcripts (Pagani 2003, Aissat 2013). However, this variant occurs in a weakly conserved amino acid (Chen 2001), and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be tolerated. This variant is reported in the ClinVar database as uncertain (Variation ID: 286406), and observed in general population databases with overall allele frequencies of 0.015 percent (2/12966 alleles, Exome Variant Server), and 0.008 percent (21/272812 alleles, Genome Aggregation Database), but is considered a low confidence variant in the database due to segmental duplication. Based on the above information, the clinical significance of p.Gly424Ser is uncertain at this time. REFERENCES Link to ClinVar database for p.Gly424Ser: https://www.ncbi.nlm.nih.gov/clinvar/variation/286406/ Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013 Jun;34(6):873-81. Chen JM et al. A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models. Mol Biol Evol. 2001 Sep;18(9):1771-88. Pagani F et al. Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. J Biol Chem. 2003 Jul 18;278(29):26580-8. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011 Apr;70(4):653-9. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2022	Identified in the single heterozygous state or with a second CFTR variant, phase unknown, in an asymptomatic individual and individuals with bronchiectasis (Puchal et al., 2011; Claustres et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25735457, 12732620, 11504857, 23420618, 21131649, 29669919, 15536480, 16251901, 28603918) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2016	The p.Gly424Ser variant in CFTR has been reported in at least 1 Caucasian indivi dual with diffuse bronchiectasis and rheumatoid arthritis. Multiple members of t his family are reported to be affected, but this variant does not segregate with disease (Puechal 2011). This variant has been identified in 9/57094 European ch romosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs371107552). Computational prediction tools and conservation analysis suggest that the p.Gly424Ser variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. In summary, the cl inical significance of the p.Gly424Ser variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2024	Variant summary: CFTR c.1270G>A (p.Gly424Ser) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.7e-05 in 247118 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (9.7e-05 vs 0.013), allowing no conclusion about variant significance. c.1270G>A has been reported in the literature in individuals affected with clinical features of Non-Classic Cystic Fibrosis (example Puechal_2011, Tamura_2018, Raraigh_2022). The Sickkids database also reports a female patient with bronchiectasis harboring this variant. These report(s) do not provide unequivocal conclusions about association of the variant with CFTR-related conditions. At least one publication reports that this variant reduced inclusion of exon 9 in a mini-gene assay to approximately 40-50% of levels observed for a wild type control, however the wild type background also demonstrated exon 9 skipping (example, Pagani_2003). The following publications have been ascertained in the context of this evaluation (PMID: 23420618, 11504857, 28603918, 15536480, 12732620, 16251901, 21131649, 25735457, 34782259, 29669919). ClinVar contains an entry for this variant (Variation ID: 286406). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.65

T;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

-0.090

N;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.46

Sift

Benign

0.075

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0

B;.

Vest4

0.72

MVP

0.99

MPC

0.0040

ClinPred

0.044

GERP RS

4.8

Varity_R

0.071

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Other links and lift over