chr16-13920197-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_005236.3(ERCC4):c.32C>T(p.Ala11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A11A) has been classified as Likely benign.
Frequency
Consequence
NM_005236.3 missense
Scores
Clinical Significance
Conservation
Publications
- xeroderma pigmentosum group FInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen
- Fanconi anemia complementation group QInheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- XFE progeroid syndromeInheritance: AR Classification: STRONG Submitted by: Ambry Genetics
- Fanconi anemiaInheritance: 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
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ERCC4 | NM_005236.3 | c.32C>T | p.Ala11Val | missense_variant | Exon 1 of 11 | ENST00000311895.8 | NP_005227.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.0000123 AC: 3AN: 243746 AF XY: 0.0000151 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1454600Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2AN XY: 723978 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Uncertain:1
This sequence change replaces alanine with valine at codon 11 of the ERCC4 protein (p.Ala11Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ERCC4-related conditions. This variant is present in population databases (rs753596005, ExAC 0.01%). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at