7-117666937-C-T

Position:

• chr7-117666937-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000492.4(CFTR):​c.4272C>T​(p.Tyr1424Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,614,018 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (60 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:19
• Conservation: PhyloP100: -2.86

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 7-117666937-C-T is Benign according to our data. Variant chr7-117666937-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93156.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=11}. Variant chr7-117666937-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.86 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.4272C>T	p.Tyr1424Tyr	synonymous_variant	27/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.4272C>T	p.Tyr1424Tyr	synonymous_variant	27/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1011 AN: 152160 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00902

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00667 AC: 1672 AN: 250688 Hom.: 14 AF XY: 0.00685 AC XY: 928 AN XY: 135512

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00539

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00323

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00868

Gnomad OTH exome AF: 0.00832

GnomAD4 exome AF: 0.00762 AC: 11137 AN: 1461740 Hom.: 60 Cov.: 31 AF XY: 0.00757 AC XY: 5507 AN XY: 727172

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00584

Gnomad4 ASJ exome AF: 0.0263

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00329

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.00827

Gnomad4 OTH exome AF: 0.00752

GnomAD4 genome AF: 0.00664 AC: 1011 AN: 152278 Hom.: 7 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74446

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00805

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.00902

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00910 Hom.: 7

Bravo AF: 0.00736

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0104

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:19

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Benign:7

Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 30, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Apr 09, 2019	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Nov 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CFTR: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2019	This variant is associated with the following publications: (PMID: 25797027, 28040058) -

CFTR-related disorder Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 13, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Nov 09, 2021	- -

Hereditary pancreatitis Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

May 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.63
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1800135; hg19: chr7-117306991; COSMIC: COSV105835521;