7-117611726-A-T

Variant names:

• chr7-117611726-A-T
• rs1800118
• NM_000492.4:c.3285A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000492.4(CFTR):​c.3285A>T​(p.Thr1095Thr) 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
• Publications: 7 publications found

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]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.051).
• 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 VariationId is 195464.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3285A>T	p.Thr1095Thr	synonymous_variant	Exon 20 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.177+4503T>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3285A>T	p.Thr1095Thr	synonymous_variant	Exon 20 of 27	1	NM_000492.4	ENSP00000003084.6

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

GnomAD2 exomes AF: 0.00455 AC: 1143 AN: 251124 AF XY: 0.00471

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 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

African (AFR) AF: 0.000926 AC: 31 AN: 33460

American (AMR) AF: 0.000739 AC: 33 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00831 AC: 217 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00341 AC: 182 AN: 53396

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00901 AC: 10017 AN: 1111728

Other (OTH) AF: 0.00505 AC: 305 AN: 60374

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

African (AFR) AF: 0.00159 AC: 66 AN: 41502

American (AMR) AF: 0.000459 AC: 7 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00293 AC: 31 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00908 AC: 617 AN: 67976

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

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

Feb 19, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16251901, 23378595, 7515303, 15536480, 7525450, 16128988, 11354633, 11788091, 10601093) -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: BP4, BP7, BS2 -

Nov 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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'. -

Cystic fibrosis Benign:6

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

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 -

Aug 17, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Mar 28, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 05, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 21, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pancreatitis Benign:1

Apr 13, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.0
DANN	Benign	0.69
PhyloP100		-1.5
PromoterAI		-0.019	Neutral
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1800118; hg19: chr7-117251780; COSMIC: COSV50040638;