rs1800118
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2
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
Consequence
NM_000492.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
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: 824AN: 151960Hom.: 8 Cov.: 31
GnomAD3 exomes AF: 0.00455 AC: 1143AN: 251124Hom.: 3 AF XY: 0.00471 AC XY: 639AN XY: 135712
GnomAD4 exome AF: 0.00738 AC: 10789AN: 1461446Hom.: 33 Cov.: 31 AF XY: 0.00731 AC XY: 5315AN XY: 727026
GnomAD4 genome ? AF: 0.00542 AC: 824AN: 152078Hom.: 8 Cov.: 31 AF XY: 0.00519 AC XY: 386AN XY: 74342
ClinVar
Submissions by phenotype
not provided Benign:7
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | CFTR: BP4, BP7, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 19, 2021 | - - |
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'. - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
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) - |
Cystic fibrosis Benign:6
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
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 | 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 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
CFTR-related disorder Uncertain:1Benign:3
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). - |
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, 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 | - - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at