rs377502207

chr7-117603781-A-Cchr7-117603781-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000492.4(CFTR):c.2907A>C(p.Ala969=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000137 in 1,461,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A969A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9906
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:1
• Conservation: PhyloP100: 4.83

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 Uncertain_significance. Variant got 3 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. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2907A>C	p.Ala969=	splice_region_variant, synonymous_variant	17/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2907A>C	p.Ala969=	splice_region_variant, synonymous_variant	17/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251120 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461394 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:2 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2019	Variant summary: CFTR c.2907A>C (p.Ala969Ala) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 5' splicing donor site, two predict the variant weakens a 5' donor site. At least one publication reported experimental evidence that this variant affects mRNA splicing, demonstrating in a minigene assay that c.2907A>C led to skipping of exon 17, predicted to result in a frameshift and a premature stop codon (Tian 2016). The variant allele was found at a frequency of 2.4e-05 in 251120 control chromosomes, exclusively observed within the East Asian subpopulation (gnomAD). c.2907A>C has been reported in the literature in a compound heterozygote Chinese individual affected with Cystic Fibrosis (Tian 2016). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 15, 2014	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	This sequence change affects codon 969 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs377502207, gnomAD 0.03%). This variant has been observed in individual(s) with congenital absence of vas deferens and/or cystic fibrosis who had a second CFTR variant (PMID: 27081564, 32777524). ClinVar contains an entry for this variant (Variation ID: 549917). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 27081564). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CFTR-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2023

The CFTR c.2907A>C variant is not predicted to result in an amino acid change (p.=). This variant is predicted to weaken the spice donor site at the exon 17/intron 17 boundary based on available splicing prediction programs (Alamut Visual Plus v1.6.1) and a functional study showed that this variant leads to skipping of exon 17 (Tian et al. 2016. PubMed ID: 27081564). This variant was reported in the compound heterozygous state in an individual with Cystic Fibrosis (C8, Tian et al. 2016. PubMed ID: 27081564) and was reported in three alleles in a study of individuals with congenital absence of the vas deferens (Table 1, No 45, Luo et al. 2021. PubMed ID: 32777524). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117243835-A-C) and has conflicting information regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain significance to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/549917/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	19
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.44		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs377502207; hg19: chr7-117243835;