7-117536648-GA-GAA

Position:

• chr7-117536648-GA-GAA

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.850dup​(p.Met284AsnfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000685 in 1,459,424 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: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 5.81

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 7-117536648-G-GA is Pathogenic according to our data. Variant chr7-117536648-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 189095.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.850dup	p.Met284AsnfsTer3	frameshift_variant	7/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.850dup	p.Met284AsnfsTer3	frameshift_variant	7/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459424 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726072

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 12, 2014	The c.850dupA pathogenic mutation (also known as 977insA), located in coding exon 7 of the CFTR gene, results from a duplication of A at nucleotide position 850, causing a translational frameshift with a predicted alternate stop codon (p.M284Nfs*3). This pathogenic mutation was first reported in an individual with mild to moderate lung disease who was pancreatic sufficient; this individual also carried the deltaF508 pathogenic mutation (Cheadle JP et al. Hum Mol Genet. 1993; 2(3):317-9). In addition to the clinical data presented in the literature, 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). -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This sequence change creates a premature translational stop signal (p.Met284Asnfs*3) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 7684644). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.977insA. ClinVar contains an entry for this variant (Variation ID: 189095). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2022	Variant summary: The variant, CFTR c.850dupA (p.Met284AsnfsX3, also known as legacy name 977insA) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.861_865delCTTAA (p.Met284fsX3), c.948delT (p.Phe316fsX12)). The variant was absent in 244174 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with Cystic Fibrosis (Cheadle_1993, Schwarz_1995). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -

CFTR-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 13, 2024	The CFTR c.850dupA variant is predicted to result in a frameshift and premature protein termination (p.Met284Asnfs*3). This variant, also described as c.844_845insA, c.845_846insA, and 977insA, has been reported in multiple individuals with cystic fibrosis, including at least eight individuals in the CFTR2 database (Cheadle et al. 1993. PubMed ID: 7684644; Trujillano et al. 2015. PubMed ID: 26436105; Park et al. 2020. PubMed ID: 33014932; https://cftr2.org/mutation/general/977insA/). In vitro functional studies on cultured nasal epithelial cells from a patient heterozygous for both p.Met284Asnfs*3 and p.Phe508del showed these cells retained only ~12% residual CFTR activity compared to control (Park et al. 2020. PubMed ID: 33014932). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 28, 2016

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs786204693; hg19: chr7-117176702;