chr2-127259306-C-A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000122.2(ERCC3):c.2207G>T(p.Arg736Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R736S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000122.2 missense
Scores
Clinical Significance
Conservation
Publications
- trichothiodystrophy 2, photosensitiveInheritance: AR Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
- xeroderma pigmentosum group BInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp
- trichothiodystrophy 1, photosensitiveInheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
- trichothiodystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- xeroderma pigmentosumInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- xeroderma pigmentosum-Cockayne syndrome complexInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.0000119 AC: 3AN: 251370 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727246 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC3 protein function. ClinVar contains an entry for this variant (Variation ID: 134122). This variant has not been reported in the literature in individuals affected with ERCC3-related conditions. This variant is present in population databases (rs587778276, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 736 of the ERCC3 protein (p.Arg736Ile). -
not specified Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at