7-117666917-G-T

Variant names:

• chr7-117666917-G-T
• rs397508707
• NM_000492.4:c.4252G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000492.4(CFTR):​c.4252G>T​(p.Glu1418*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,732 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.04
• Publications: 2 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117666917-G-T is Pathogenic according to our data. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-117666917-G-T is described in CliVar as Pathogenic. Clinvar id is 53934.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.4252G>T	p.Glu1418*	stop_gained	Exon 27 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.4252G>T	p.Glu1418*	stop_gained	Exon 27 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461732 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic fibrosis Pathogenic:2

Jun 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CFTR protein in which other variant(s) (p.Gln1476*) have been determined to be pathogenic (PMID: 11938439, 22020151, 25910067, 28544683, 30444886). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects CFTR function (PMID: 30444886). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 53934). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 20522854). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1418*) in the CFTR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 63 amino acid(s) of the CFTR protein. -

Sep 20, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.0
Vest4		0.71
GERP RS		4.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397508707; hg19: chr7-117306971;