rs397508595

Positions:

• chr7-117627810-A-G

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]

(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/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3717+40A>G		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3717+40A>G		intron_variant		1	NM_000492.4	ENSP00000003084	P2
	ENST00000456270.1	n.66-11470T>C		intron_variant, non_coding_transcript_variant		3

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:6

Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2023	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 disrupted 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 introduces a premature termination codon (PMID: 28475858). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 23, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 30, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 05, 2022	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2022	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. -

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

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 18, 2021

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

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 13, 2019

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 12, 2024

- -

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;