rs1800118

chr7-117611726-A-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.3285A>T(p.Thr1095=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0072 in 1,613,524 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1095T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (33 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:20
• Conservation: PhyloP100: -1.54

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 7-117611726-A-T is Benign according to our data. Variant chr7-117611726-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195464.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=7, Uncertain_significance=1}. Variant chr7-117611726-A-T is described in Lovd as [Likely_benign]. Variant chr7-117611726-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3285A>T	p.Thr1095=	synonymous_variant	20/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3285A>T	p.Thr1095=	synonymous_variant	20/27	1	NM_000492.4	P2
	ENST00000456270.1	n.177+4503T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00542 AC: 824 AN: 151960 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00908

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00455 AC: 1143 AN: 251124 Hom.: 3 AF XY: 0.00471 AC XY: 639 AN XY: 135712

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00817

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00738 AC: 10789 AN: 1461446 Hom.: 33 Cov.: 31 AF XY: 0.00731 AC XY: 5315 AN XY: 727026

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.000739

Gnomad4 ASJ exome AF: 0.00831

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00341

Gnomad4 NFE exome AF: 0.00901

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.00542 AC: 824 AN: 152078 Hom.: 8 Cov.: 31 AF XY: 0.00519 AC XY: 386 AN XY: 74342

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00293

Gnomad4 NFE AF: 0.00908

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00804 Hom.: 2

Bravo AF: 0.00530

EpiCase AF: 0.00737

EpiControl AF: 0.00735

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:20

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	This variant is associated with the following publications: (PMID: 16251901, 23378595, 7515303, 15536480, 7525450, 16128988, 11354633, 11788091, 10601093) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CFTR: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2017	Variant summary: This silent variant CFTR c.3285A>T (p.Thr1095Thr), alternatively known as 3417A>T, is located at a non-conserved position in exon 20 of CFTR and it is 82 nucleotides upstream to the nearest exon-intron junction. The variant is not predicted to impact splicing by 5/5 splice prediction tools. ESEfinder predicts the loss of a SC35 binding motif and Mutation Taster predicts as disease-causing. However, predictions from in silico tools are not definitive. There are no experimental in vitro or in vivo functional studies reported for the variant at this time. It has been observed in patients with infertility (non-obstructive infertility, oligoasthenoteratozoospermia and oligoasthenoteratozoospermia), pancreatitis, sarcoidosis, bronchiectasis and COPD. While CFTR mutations may represent a risk factor for these phenotypes, there is a lack of conclusive evidence. Multiple studies have reported this variant to occur in controls and patients at similar frequencies, suggesting that this variant is unlikely to be a risk allele. There are two reports in which this variant was found with CFin 1 German family and in 1 patient referred to CF testing. However, in both studies, cosegregation and/or co-occurrence information is not provided and authors refer to this variant as a polymorphism. This variant was found in 590/124728 control chromosomes (2 homozygotes) including ExAC at an allele frequency of 0.0047303, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). This population frequency supports benign outcome for phenotypes other than CF and CBAVD. Most publications spanning over a decade (1994-2009) report this variant as a polymorphism (Ravnik-Glavac 2001, Gallati 2009, Dork 1994, Tzetis 2001, Shackelton 1994). Multiple clinical laboratories/reputable database have classified this variant as likely benign/benign. Taken together, this variant is classified as 'Benign'. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 19, 2021	- -

Cystic fibrosis Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 05, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: BS2, BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 13, 2015	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. -

CFTR-related disorder Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 05, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 01, 2023	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2015	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr1095Thr in exon 20 of CFTR: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.7% (57/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800118). -

Hereditary pancreatitis Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	1.0
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1800118; hg19: chr7-117251780; COSMIC: COSV50040638;