rs397508595

Variant names:

• chr7-117627810-A-G
• rs397508595
• NM_000492.4:c.3717+40A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-117627810-A-G
• chr7-117627810-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.3717+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 1.12

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]

ENSG00000083622 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117627810-A-G is Pathogenic according to our data. Variant chr7-117627810-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 53789.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117627810-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.3717+40A>G		intron_variant	Intron 22 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3717+40A>G		intron_variant	Intron 22 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Oct 11, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

May 05, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -

Aug 23, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nov 30, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3717+40A>G intronic variant results from an A to G substitution 40 nucleotides after coding exon 22 in the CFTR gene. This variant was identified in two siblings with elevated sweat chloride levels and p.F508del confirmed in trans; one sibling had asymptomatic diffuse bronchiectasis and pancreatic sufficiency while the second sibling had diffuse bronchiectasis with recurrent bronchopulmonary infections, pancreatic insufficiency, nasal polyps, and recurrent sinusitis (Priou-Guesdon M et al. Ann. Endocrinol. (Paris), 2010 Feb;71:46-50). Another individual heterozygous for c.3717+40A>G and p.F508del was described as having mild CF based on late diagnosis (at age 14) and pancreatic sufficiency (Lee M et al. Am J Hum Genet, 2017 May;100:751-765). In one study, reverse transcription PCR (RT-PCR) on nasal epithelial cells from a patient with cystic fibrosis (heterozygous for c.3717+40A>G and p.Phe508del) was performed. Results indicated that this variant results in the retention of the first 40 nucleotides of intron 22. In addition, a minigene expression assay suggests this variant results in leaky splicing, as evidenced by the presence of both fully glycosylated and immature core-glycosylated CFTR protein on Western blot analysis (Lee M et al. Am J Hum Genet, 2017 May;100:751-765). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Jan 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.3717+40A>G variant (rs397508595) is reported in the literature in multiple individuals affected with cystic fibrosis and one individual with congenital bilateral absence of the vas deferens (Lee 2017, Steiner 2011, CFTR2 database). In addition, this variant has been observed in testing performed at ARUP Laboratories in an individual with elevated sweat chloride and a second pathogenic variant. The c.3717+40A>G variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. Indeed, functional studies of this variant demonstrate it leads to the inclusion of 40 additional nucleotides, causing a frameshift and decreased mRNA levels (Lee 2017). Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org/ Lee M et al. Systematic Computational Identification of Variants That Activate Exonic and Intronic Cryptic Splice Sites. Am J Hum Genet. 2017;100(5):751-765. PMID: 28475858. 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):912-920. PMID: 21520337. -

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cystic fibrosis or congenital absence of the vas deferens (PMID: 23974870, 28475858). This variant is also known as 3849+40A>G. ClinVar contains an entry for this variant (Variation ID: 53789). Studies have shown that this variant results in activation of a cryptic donor 40 nucleotides downstream of the exon 22 canonical donor, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 28475858). For these reasons, this variant has been classified as Pathogenic. -

CFTR-related disorder Pathogenic:1

Dec 13, 2019

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1

Jan 18, 2021

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	24
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 0
DS_DL_spliceai		0.29		Position offset: -40

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508595; hg19: chr7-117267864;