rs371315549

Positions:

• chr7-117530893-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000492.4(CFTR):​c.274-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,587,290 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: CFTR NM_000492.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003449
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: -0.217

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-117530893-T-C is Benign according to our data. Variant chr7-117530893-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237855.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=12, Benign=1, Uncertain_significance=2}. Variant chr7-117530893-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.274-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.274-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

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: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000467 AC: 117 AN: 250412 Hom.: 0 AF XY: 0.000539 AC XY: 73 AN XY: 135342

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000821

Gnomad OTH exome AF: 0.000656

GnomAD4 exome AF: 0.000872 AC: 1252 AN: 1434974 Hom.: 1 Cov.: 28 AF XY: 0.000852 AC XY: 610 AN XY: 715630

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000382

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000818

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00109

Gnomad4 OTH exome AF: 0.000588

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74482

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000892 Hom.: 0

Bravo AF: 0.000540

EpiCase AF: 0.000927

EpiControl AF: 0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2020	This variant is associated with the following publications: (PMID: 32429104, 10571949, 10601093, 10746558, 11938439, 21499205, 23381846, 21708286, 20717170, 15858154, 21198395, 7691344, 21520337, 25087612, 25781545, 25525159, 17020467, 15758663) -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2016	Variant summary: The c.274-6T>C in CFTR gene is an intronic variant that affects a non-conserved nucleotide located at a position not widely known to affect splicing. 5/5 in silico tools predict no significant effects on splicing and these predictions been confirmed by in vitro/vivo studies (Raynal , 2013). Variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0005 (59/114809 chrs tested) predominantly in individuals of Non-Finnish European ancestry. Although the observed frequency does not exceed the maximal expected allele frequency of a disease causing allele (0.006), it is more than carrier frequency of all known splice acceptor mutations in ExAC cohort, indicating it is rare polymorphism. The variant was reported in several CF-RD spectrum patients without strong evidence for pathogenicity as well as in unaffected controls. Clinical diagnostic centers classify variant as Benign/VUS without evidence to independently evaluate. Taking together, the variant was classified as Likely Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 02, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	CFTR: BP4 -

Cystic fibrosis Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 07, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 22, 2019	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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not reported. No information available. Gene not associated to pt disease. -

CFTR-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary pancreatitis Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Aug 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs371315549; hg19: chr7-117170947;