rs397508630

Positions:

• chr7-117652850-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.3883del​(p.Ile1295PhefsTer33) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000741 in 1,349,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 3.86

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117652850-TA-T is Pathogenic according to our data. Variant chr7-117652850-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 53839.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117652850-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3883del	p.Ile1295PhefsTer33	frameshift_variant	24/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3883del	p.Ile1295PhefsTer33	frameshift_variant	24/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1349346 Hom.: 0 Cov.: 23 AF XY: 0.00000148 AC XY: 1 AN XY: 677298

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.88e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 13, 2021	This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 32429104). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile1295Phefs*33) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). ClinVar contains an entry for this variant (Variation ID: 53839). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 2015	The c.3883delA pathogenic mutation, located in coding exon 24 of the CFTR gene, results from a deletion of one nucleotide at position 3883, causing a translational frameshift with a predicted alternate stop codon. This mutation has been observed in 3 patients in the CFTR2 database, two of these patients were reported to have a deltaF508 mutation in trans. Pancreatic insufficiency and pulmonary symptoms were observed in these patients (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7, Supplementary Table and The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed February 10, 2015). Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). Based on the supporting evidence, c.3883delA is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs397508630; hg19: chr7-117292904;