rs773739166

Variant names:

• chr7-117509142-G-A
• rs773739166
• NM_000492.4:c.273G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117509142-G-A
• chr7-117509142-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000492.4(CFTR):​c.273G>A​(p.Gly91Gly) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000746 in 1,340,158 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G91G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.71
• Publications: 6 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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.273G>A	p.Gly91Gly	splice_region_variant, synonymous_variant	Exon 3 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.273G>A	p.Gly91Gly	splice_region_variant, synonymous_variant	Exon 3 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250594 AF XY: 0.00000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1340158 Hom.: 0 Cov.: 22 AF XY: 0.00000148 AC XY: 1 AN XY: 673798

African (AFR) AF: 0.00 AC: 0 AN: 31070

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25422

East Asian (EAS) AF: 0.00 AC: 0 AN: 39064

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5442

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1001620

Other (OTH) AF: 0.00 AC: 0 AN: 56220

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:2

Jun 02, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM2_SUP,PP3 -

Sep 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 91 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 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs773739166, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.273G nucleotide in the CFTR gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 25636364, 27264265). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.89
PhyloP100		7.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.67		Position offset: 0

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

Other links and lift over

dbSNP: rs773739166; hg19: chr7-117149196; COSMIC: COSV50081690; COSMIC: COSV50081690;