7-117542074-T-G

Position:

• chr7-117542074-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.1175T>G​(p.Val392Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,450,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 7.13

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 7-117542074-T-G is Pathogenic according to our data. Variant chr7-117542074-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53207.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, not_provided=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1175T>G	p.Val392Gly	missense_variant	9/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1175T>G	p.Val392Gly	missense_variant	9/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450210 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 722456

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:5 Uncertain:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Oct 12, 2023	The CFTR:c.1175T>G variant is identified in the homozygous state in a 2 month female presenting with respiratory distress and laboratory findings of hyponatremia and hypocalemia. These clinical findings are suggestive of ? Pseudo-bartter phenotype of Cystic Fibrosis. As per available resources, this variant is absent from the gnomAD databases, and have a revel score of 0.8 (Deleterious). This variant has been previously reported [PMID:25097766 ]. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Jun 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 392 of the CFTR protein (p.Val392Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 25097766, 35273129). ClinVar contains an entry for this variant (Variation ID: 53207). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.1175T>G (p.Val392Gly) variant in CFTR gene has been reported previously in multiple individuals affected with cystic fibrosis (Bulegenova et al., 2022; Al-Sadeq et al., 2019; Fass et al., 2014; Rosenfeld et al., 2019). The p.Val392Gly variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Val392Gly in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 392 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 03, 2023	The p.V392G pathogenic mutation (also known as c.1175T>G), located in coding exon 9 of the CFTR gene, results from a T to G substitution at nucleotide position 1175. The valine at codon 392 is replaced by glycine, an amino acid with dissimilar properties. This mutation has been reported in several individuals with a clinical diagnosis of cystic fibrosis with elevated sweat chloride levels in conjunction with a second CFTR alteration; however, phase information was not provided (Rosenfeld M et al. Lancet Respir Med, 2018 Jul;6:545-553; Al Oraimi S et al. Oman Med J, 2022 Nov;37:e444). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 23, 2022	CFTR c.1175T>G has been identified in multiple individuals with features of cystic fibrosis who also have a second CFTR variant, although the phase of these variants is not known. This variant has been reported in ClinVar (Variation ID: 53207) but is absent from a large population dataset. BayPR, an algorithm that uses population data to assign disease liability to variants, predicts that this variant is highly likely to be CF-causing. Three bioinformatic tools queried predict that this substitution would be damaging and the valine residue at this position is evolutionarily conserved across most species assessed. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of CFTR c.1175T>G to be uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;.;.;.;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D;.;.;D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.83
MutPred		0.84		Loss of stability (P = 0.0288);Loss of stability (P = 0.0288);Loss of stability (P = 0.0288);.;Loss of stability (P = 0.0288);
MVP		1.0
MPC		0.0039
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397508170; hg19: chr7-117182128;