rs76649725

Positions:

• chr7-117642484-C-A
• chr7-117642484-C-T

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.3764C>A​(p.Ser1255Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 1.42

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 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 7-117642484-C-A is Pathogenic according to our data. Variant chr7-117642484-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 7125.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117642484-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3764C>A	p.Ser1255Ter	stop_gained	23/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3764C>A	p.Ser1255Ter	stop_gained	23/27	1	NM_000492.4	ENSP00000003084	P2
	ENST00000456270.1	n.65+4867G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251034 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135670

Gnomad AFR exome AF: 0.000123

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461402 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726994

Gnomad4 AFR exome AF: 0.0000897

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000182 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 07, 2019	NM_000492.3(CFTR):c.3764C>A(S1255*) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 26708955. Classification of NM_000492.3(CFTR):c.3764C>A(S1255*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change creates a premature translational stop signal (p.Ser1255*) 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 present in population databases (rs76649725, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 2233965, 26708955). ClinVar contains an entry for this variant (Variation ID: 7125). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 13, 1990	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 07, 2022	The p.S1255* pathogenic mutation (also known as c.3764C>A), located in coding exon 23 of the CFTR gene, results from a C to A substitution at nucleotide position 3764. This changes the amino acid from a serine to a stop codon within coding exon 23. In one study, this mutation was seen in an individual with pancreatic disease, mild pulmonary involvement, and a second nonsense alteration confirmed in trans (Cutting GR et al. N. Engl. J. Med., 1990 Dec;323:1685-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2019	The CFTR c.3764C>A; p.Ser1255Ter variant (rs76649725) is reported in the literature in multiple individuals affected with cystic fibrosis (Behar 2017, Cutting 1990, Macek 1997, CFTR2 database). In at least one affected individual, this variant was confirmed in trans to a second pathogenic variant (Cutting 1990). Several other reports indicate this variant also occurs in cis to a missense variant, p.Ile1203Val (Behar 2017, Cutting 1992). The p.Ser1255Ter variant is found on only two chromosomes (2/251034 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Behar DM et al. Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening. Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. Cutting GR et al. Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians. Am J Hum Genet. 1992 Jun;50(6):1185-94. Cutting GR et al. Two patients with cystic fibrosis, nonsense mutations in each cystic fibrosis gene, and mild pulmonary disease. N Engl J Med. 1990 Dec 13;323(24):1685-9. Macek M Jr et al. Identification of common cystic fibrosis mutations in African-Americans with cystic fibrosis increases the detection rate to 75%. Am J Hum Genet. 1997 May;60(5):1122-7. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 28, 2022	PM2, PM3_strong, PVS1 -

CFTR-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 13, 2024	The CFTR c.3764C>A variant is predicted to result in premature protein termination (p.Ser1255*). This variant is well-established to be causative for cystic fibrosis (see for example Tsui et al 1992. PubMed ID: 1284534; Sosnay PR et al 2013. PubMed ID: 23974870; cftr2.org). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Nonsense variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 05, 2018

Variant summary: CFTR c.3764C>A (p.Ser1255X) 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 (e.g. p.Leu1258fsX7, p.Trp1282X, p.Ile1295fsX32). The variant allele was found at a frequency of 4.1e-06 in 245776 control chromosomes (gnomAD). c.3764C>A has been reported in the literature in individuals affected with Cystic Fibrosis (Cutting_1992, Macek_1997, Sugarman_2004, Sontag_2016). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.17	N
MutationTaster	Benign	1.0	A;A
Vest4		0.90
GERP RS		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs76649725; hg19: chr7-117282538;