rs397508328

Variant names:

• chr7-117480095-A-G
• rs397508328
• NM_000492.4:c.1A>G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000041 in 1,461,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CFTR NM_000492.4 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 4.56

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 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 30 pathogenic variants. Next in-frame start position is after 82 codons. Genomic position: 117509113. Lost 0.055 part of the original CDS.
• PS1: Another start lost variant in NM_000492.4 (CFTR) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117480095-A-G is Pathogenic according to our data. Variant chr7-117480095-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 53423.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117480095-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1A>G	p.Met1?	start_lost	Exon 1 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1A>G	p.Met1?	start_lost	Exon 1 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251166 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:8

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Sep 06, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the CFTR gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This alteration has been reported in individuals with cystic fibrosis or congenital bilateral absence of vas deferens (des Georges M et al. J. Cyst. Fibros., 2004 Dec;3:265-72; Steiner B et al. Hum. Mutat., 2011 Aug;32:912-20; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Although alternative translation initiation has been suggested for CFTR, mutant proteins were shown to be unstable and failed membrane translocation (Carroll TP et al. J. Biol. Chem., 1995 May;270:11941-6; Ramalho AS et al. Cell. Physiol. Biochem., 2009 Nov;24:335-46). In addition, functional studies have suggested that this alteration resulted in deficient protein maturation and subsequently abolished channel conductivity (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 23, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 21, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251892 control chromosomes (gnomAD). c.1A>G has been reported in the literature in multiple individuals affected with Classic Cystic Fibrosis (Cheadle_1993, Cheadle_1994, desGeorges_2004, Gelfi_1996, Dugueperoux_2005, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and results in severe defects in CFTR mRNA expression, CFTR maturation and chloride transport (VanGoor_2014). Four ClinVar submitters, including one expert panel (CFTR2), (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CFTR mRNA. The next in-frame methionine is located at codon 82. This variant is present in population databases (rs397508328, gnomAD 0.004%). Disruption of the initiator codon has been observed in individual(s) with cystic fibrosis (PMID: 22299590, 27086061). ClinVar contains an entry for this variant (Variation ID: 53423). For these reasons, this variant has been classified as Pathogenic. -

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

CFTR-related disorder Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 11, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1A>G; p.Met1? variant (rs397508328) has been described in several individuals diagnosed with cystic fibrosis, and often associated with pancreatic insufficiency (see link to CFTR2 database). It is reported as pathogenic in ClinVar (Variation ID: 53423) and observed in the European (Non-Finnish) population at a low overall frequency of 0.004% (5/111584 alleles) in the Genome Aggregation Database. This variant affects the translation initiation codon of the CFTR gene and in vitro functional studies of this variant demonstrate severe defects in CFTR maturation and chloride transport (<1% of wildtype) (Van Goor 2014). In addition, other variants that affect the start codon in exon 1 (c.2T>C, c.2T>A, c.3G>T) have been described in individuals with pancreatic insufficient cystic fibrosis and are considered pathogenic (Bienvenu 2005, Claustres 1993, Hughes 1996). Based on available information, this variant is considered pathogenic. References: CFTR2 database: https://cftr2.org/ Bienvenu T et al. Spectrum of CFTR mutations on Réunion Island: impact on neonatal screening. Hum Biol. 2005 Oct;77(5):705-14. Claustres M et al. Analysis of the 27 exons and flanking regions of the cystic fibrosis gene: 40 different mutations account for 91.2% of the mutant alleles in southern France. Hum Mol Genet. 1993 Aug;2(8):1209-13. Hughes D et al. Mutation characterization of CFTR gene in 206 Northern Irish CF families: thirty mutations, including two novel, account for approximately 94% of CF chromosomes. Hum Mutat. 1996;8(4):340-7. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.;.;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	-0.044	T
PROVEAN	Benign	-1.0	N;.;.;N;.
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.86	P;.;.;.;.
Vest4		0.95
MutPred		0.98		Loss of glycosylation at P5 (P = 0.1081);Loss of glycosylation at P5 (P = 0.1081);Loss of glycosylation at P5 (P = 0.1081);Loss of glycosylation at P5 (P = 0.1081);Loss of glycosylation at P5 (P = 0.1081);
MVP		0.98
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.95
gMVP		0.73

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: rs397508328; hg19: chr7-117120149;