chr7-117610668-AGG-A

Variant names:

• chr7-117610668-AGG-A
• rs397508505
• NM_000492.4:c.3139_3139+1delGG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.3139_3139+1delGG​(p.Gly1047GlnfsTer28) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,148 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G1047G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CFTR NM_000492.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 9.54
• Publications: 1 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Pathogenic. The variant received 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 7-117610668-AGG-A is Pathogenic according to our data. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610668-AGG-A is described in CliVar as Pathogenic. Clinvar id is 53660.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3139_3139+1delGG	p.Gly1047GlnfsTer28	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 19 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.177+5559_177+5560delCC		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3139_3139+1delGG	p.Gly1047GlnfsTer28	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 19 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Oct 02, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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. -

Aug 16, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.3139_3139+1delGG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Two predict the variant abolishes a 3' acceptor site. Two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250734 control chromosomes (gnomAD). The variant, c.3139_3139+1delGG has been reported in the literature in multiple individuals affected with Cystic Fibrosis predominantly in Hispanic population (Wong_2004, Schrijver_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant has been reviewed by an expert panel (CFTR2) in ClinVar and they classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 19 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with CFTR-related conditions (PMID: 11668613; Invitae). This variant is also known as c.3271delGG. ClinVar contains an entry for this variant (Variation ID: 53660). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

May 03, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 3139_3139+1delGG variant results from a deletion of 1 nucleotide located at position 3139 as well as a deletion of the first intronic nucleotide after coding exon 19 of the CFTR gene. This alteration, described as 3277delGG, was detected in a patient with an elevated sweat chloride, reduced lung function, Pseudomonas infection, pancreatic insufficiency, and another CFTR pathogenic variant (phase not confirmed) (Wong LJ et al. Hum Mutat. 2001 Oct;18:296-307). This alteration, described as 3277delGG, was also detected in at least one Hispanic individual from a cohort of patients with cystic fibrosis (Schrijver I et al. J Mol Diagn. 2016 Jan;18:39-50). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). The canonical splice donor site is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, the exact impact of this deletion on CFTR splicing and function is currently unknown. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

CFTR-related disorder Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs397508505; hg19: chr7-117250722;