rs121908797

chr7-117606753-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):c.2988G>A(p.Gln996=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000072 in 1,527,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9954
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 9.25

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117606753-G-A is Pathogenic according to our data. Variant chr7-117606753-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 35857.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117606753-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2988G>A	p.Gln996=	splice_region_variant, synonymous_variant	18/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2988G>A	p.Gln996=	splice_region_variant, synonymous_variant	18/27	1	NM_000492.4	P2
	ENST00000456270.1	n.178-1764C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151736 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251008 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000436 AC: 6 AN: 1376222 Hom.: 0 Cov.: 23 AF XY: 0.00000435 AC XY: 3 AN XY: 690016

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: 0.00000580

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151736 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74056

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000554 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2020	Variant summary: CFTR c.2988G>A (p.Gln996Gln) alters a last conserved nucleotide located at the end of exon 18 adjacent to a canonical splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. Several publications report experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 18 (legacy exon 16) (example, Zielendki_1994 (unpublished abstract), Sosnay_2013). The variant allele was found at a frequency of 4e-06 in 251008 control chromosomes. c.2988G>A has been widely reported in the literature in multiple individuals affected with Cystic Fibrosis (example, Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories and one expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 29, 2023	This sequence change affects codon 996 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121908797, gnomAD 0.002%). This variant has been observed in individuals with clinical features of cystic fibrosis (PMID: 16436646, 23974870). This variant is also known as 3120G>A. ClinVar contains an entry for this variant (Variation ID: 35857). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 23974870, 25066652). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_VSTR, PP3 -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 04, 2022	The c.2988G>A pathogenic mutation (also known as c.3120G>A and p.Q996Q), located in coding exon 18 of the CFTR gene, results from a G to A substitution at nucleotide position 2988. This nucleotide substitution does not change the amino acid at codon 996. However, this change occurs in the last base pair of coding exon 18, which makes it likely to have some effect on normal mRNA splicing. In one study, this mutation produces transcripts that skip exon 18 with no detectable CFTR protein via a mini gene assay (Sharma N et al. Hum. Mutat., 2014 Oct;35:1249-59). In another study, this mutation was described in an individual with elevated sweat chloride levels and pancreatic sufficiency (Wilschanski M et al. J. Pediatr., 1995 Nov;127:705-10). In addition, this mutation was detected in the homozygous state in an individual who presented for carrier screening and was subsequently found to have an elevated sweat chloride level (Heaney DL et al. J Mol Diagn, 2006 Feb;8:137-40). This mutation is associated with increased sweat chloride levels, varying presentations of pancreatic insufficiency, and decreased lung function (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000492.3(CFTR):c.2988G>A(aka Q996=) is classified as pathogenic in the context of cystic fibrosis. Please note that Q996= is associated with a broad spectrum of disease, ranging from clinically asymptomatic to classic cystic fibrosis. Sources cited for classification include the following: PMID 23974870 and 16436646. Classification of NM_000492.3(CFTR):c.2988G>A(aka Q996=) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2021	PVS1, PS3, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	The CFTR c.2988G>A; p.Gln996= variant (rs121908797), also known as 3120G>A for traditional nomenclature, is reported in multiple individuals with cystic fibrosis, though with varying pancreatic sufficiency (CFTR2 database, Sosnay 2013, Wilschanski 1995). Functional characterization of the variant indicates splicing defects leading to the absence of full-length mRNA and the generation of an aberrant transcript (Sharma 2014, Sosnay 2013, Wilschanski 1995). This variant is also reported in ClinVar (Variation ID: 35857). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant weakens the nearby canonical donor splice site, consistent with functional studies. Based on available information, this variant is considered to be pathogenic. REFERENCES CFTR2 database: http://cftr2.org/ Sharma N et al. Experimental assessment of splicing variants using expression minigenes and comparison with in silico predictions. Hum Mutat. 2014 Oct;35(10):1249-59. PMID: 25066652. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. Wilschanski M et al. Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations. J Pediatr. 1995 Nov;127(5):705-10. PMID: 7472820. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 05, 2019	The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908797; hg19: chr7-117246807;