rs74467662

chr7-117509145-A-Cchr7-117509145-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):c.273+3A>C variant causes a splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFTR NM_000492.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 3.59

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 Pathogenic. Variant got 12 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 7-117509145-A-C is Pathogenic according to our data. Variant chr7-117509145-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 35846.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117509145-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.273+3A>C		splice_donor_region_variant, intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.273+3A>C		splice_donor_region_variant, intron_variant		1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2020	The c.273+3A>C intronic variant results from an A to C substitution 3 nucleotides after coding exon 3 in the CFTR gene. In one study, this variant was identified in two African American individuals with cystic fibrosis (CF) and it has been described as a common African American CF mutation (Macek M et al. Am. J. Hum. Genet., 1997 May;60:1122-7). In our internal cohort, this variant was identified with a known CF mutation in multiple diagnostic cases in our laboratory; however, the phase is not known (Ambry internal data). This nucleotide position is conserved in available vertebrate species. This variant was not reported in the gnomAD database, with coverage at this position. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 9150159 and 11388756. Classification of NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is based on the following criteria: This variant 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2023	Variant summary: CFTR c.273+3A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict the variant weakens a canonical 5' donor site and one predicts it abolishes the site. In support of the predicted effect on splicing, Macek et al. point out that cytosine is the least common nucleotide at the +3 position of splice-donor sites, and that mutations at this location have been reported to cause aberrant RNA splicing (Macek_1997). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250744 control chromosomes (gnomAD). c.273+3A>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Macek_1997, Watson_2004, Dork_1998, Raraigh_2022, Bresnick_2021), and at least one family was reported as compound heterozygous with another pathogenic variant. In addition, the CFTR2 database reports 10 patients with this variant, stating that this variant causes CF when combined with another CF-causing variant (average sweat chloride levels in patients harboring this variant was found to be 109 mEq/L and 100% of these patients were pancreatic insufficient). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 15371902, 15025720, 16049310, 9950364, 12089190, 20616359, 9150159, 21796730, 16244288, 11471192, 22975760, 26708955, 9683582, 34782259, 34857524). Four submitters, including an expert panel (CFTR2), have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 35846). This variant is also known as 405+3A>C. This variant has been observed in individuals with cystic fibrosis (PMID: 23974870). This sequence change falls in intron 3 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. It affects a nucleotide within the consensus splice site. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 07, 2022

PP3, PM2, PM3_very_strong -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	15
Dann	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs74467662; hg19: chr7-117149199;