7-117540171-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000492.4(CFTR):c.941G>T(p.Gly314Val) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G314E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.94

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 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117540171-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54089.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, not_provided=1, Uncertain_significance=2, Pathogenic=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 7-117540171-G-T is Pathogenic according to our data. Variant chr7-117540171-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2691472.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.941G>T	p.Gly314Val	missense_variant	8/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.941G>T	p.Gly314Val	missense_variant	8/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic fibrosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 06, 2023

Variant summary: CFTR c.941G>T (p.Gly314Val) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251236 control chromosomes (gnomAD). c.941G>T has been reported in the literature in at-least one individual affected with Cystic Fibrosis (example: Claustres_2000). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same residue (p.Gly314Glu) has been classified pathogenic in ClinVar (CV ID 54089 ). The following publication has been ascertained in the context of this evaluation (PMID: 10923036). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.8	L;.;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.0	N;.;.;N;.
REVEL	Pathogenic	0.75
Sift	Benign	0.031	D;.;.;D;.
Sift4G	Uncertain	0.0020	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.92
MutPred		0.89		Loss of glycosylation at S313 (P = 0.032);Loss of glycosylation at S313 (P = 0.032);Loss of glycosylation at S313 (P = 0.032);.;Loss of glycosylation at S313 (P = 0.032);
MVP		0.99
MPC		0.010
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75763344; hg19: chr7-117180225;