rs148104494
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BP6
The NM_002528.7(NTHL1):c.274C>T(p.Arg92Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0013 in 1,613,166 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R92H) has been classified as Uncertain significance.
Frequency
Consequence
NM_002528.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTHL1 | NM_002528.7 | c.274C>T | p.Arg92Cys | missense_variant | 2/6 | ENST00000651570.2 | |
NTHL1 | NM_001318193.2 | c.274C>T | p.Arg92Cys | missense_variant | 2/5 | ||
NTHL1 | XM_047434171.1 | c.-6C>T | 5_prime_UTR_variant | 2/6 | |||
NTHL1 | NM_001318194.2 | c.24+72C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTHL1 | ENST00000651570.2 | c.274C>T | p.Arg92Cys | missense_variant | 2/6 | NM_002528.7 |
Frequencies
GnomAD3 genomes ? AF: 0.000894 AC: 136AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000916 AC: 230AN: 250962Hom.: 0 AF XY: 0.000986 AC XY: 134AN XY: 135846
GnomAD4 exome AF: 0.00134 AC: 1961AN: 1460922Hom.: 2 Cov.: 32 AF XY: 0.00136 AC XY: 991AN XY: 726736
GnomAD4 genome ? AF: 0.000887 AC: 135AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60AN XY: 74438
ClinVar
Submissions by phenotype
not provided Uncertain:5Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 19, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian cancer, breast cancer, and leukemia (Li et al., 2019; Byrjalsen et al., 2020; Li et al., 2021); This variant is associated with the following publications: (PMID: 30584090, 29641532, 33980861, 33332384, 20054297, 32906206) - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | NTHL1: BP1 - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 09, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 08, 2016 | - - |
Familial adenomatous polyposis 3 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Dec 21, 2021 | The NTHL1 c.298C>T (p.Arg100Cys) missense change has a maximum subpopulation frequency of 0.13% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-2096209-G-A). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported as individuals with colorectal cancer, breast cancer and precursor B-cell acute lymphoblastic leukemia (PMID: 32620917, 32295625, 32620917). It has also been identified in 3/1358 non-cancer controls collected as part of a study of individuals with multiple primary cancers (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with familial adenomatous polyposis. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 30, 2021 | - - |
NTHL1-related condition Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 04, 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at