rs397508562

Variant names:

• chr7-117614684-G-A
• rs397508562
• NM_000492.4:c.3439G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000492.4(CFTR):​c.3439G>A​(p.Val1147Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 6.41

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a transmembrane_region Helical; Name=12 (size 20) in uniprot entity CFTR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3439G>A	p.Val1147Ile	missense_variant	Exon 21 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3439G>A	p.Val1147Ile	missense_variant	Exon 21 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.3439G>A (p.Val1147Ile) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251082 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3439G>A has been reported in the literature in the heterozygous state in at least 1 individual affected with Cystic Fibrosis (example, Kilinc_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12439892). ClinVar contains an entry for this variant (Variation ID: 53742). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cystic fibrosis Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.9	L;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.73	N;.;.;N;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.023	D;.;.;D;.
Sift4G	Benign	0.080	T;.;.;T;.
Polyphen		0.12	B;.;.;.;.
Vest4		0.28
MutPred		0.86		Gain of catalytic residue at S1149 (P = 0.1316);.;.;.;.;
MVP		0.94
MPC		0.0049
ClinPred		0.93	D
GERP RS		5.9
Varity_R		0.52
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397508562; hg19: chr7-117254738; COSMIC: COSV50126448;