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. The variant received 15 ACMG points: 15P and 0B. PS3 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 (★★★). ClinVar reports functional evidence for this variant: "SCV001472091: Functional studies of this variant demonstrate it leads to the inclusion of 40 additional nucleotides, causing a frameshift and decreased mRNA levels (Lee 2017). PMID:28475858" and additional evidence is available in ClinVar.

• 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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001472091: Functional studies of this variant demonstrate it leads to the inclusion of 40 additional nucleotides, causing a frameshift and decreased mRNA levels (Lee 2017). PMID: 28475858; SCV001591261: 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).; SCV002623114: 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).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 53789.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.3717+40A>G		intron	N/A	NP_000483.3
	CFTR-AS2	NR_199597.1		n.66-11470T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3717+40A>G		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000649406.1		c.*10A>G		3_prime_UTR	Exon 21 of 21	ENSP00000497965.1	A0A3B3ITW5
	CFTR	ENST00000648260.1		c.*10A>G		3_prime_UTR	Exon 17 of 17	ENSP00000497957.1	A0A3B3ITW0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Cystic fibrosis (7)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	CFTR-related disorder (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Uncertain	24
DANN	Benign	0.86
PhyloP100		1.1
Mutation Taster		=28/72	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397508595; hg19: chr7-117267864;