chr2-176092922-G-C
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_000523.4(HOXD13):āc.32G>Cā(p.Gly11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,329,670 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000523.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000857 AC: 130AN: 151682Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000185 AC: 7AN: 37778Hom.: 0 AF XY: 0.000299 AC XY: 7AN XY: 23412
GnomAD4 exome AF: 0.000454 AC: 535AN: 1177880Hom.: 4 Cov.: 30 AF XY: 0.000438 AC XY: 252AN XY: 575020
GnomAD4 genome AF: 0.000856 AC: 130AN: 151790Hom.: 1 Cov.: 33 AF XY: 0.000903 AC XY: 67AN XY: 74196
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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The G11A variant has been published previously in association with a synpolydactyly phenotype; the homozygous proband was more severely affected than the heterozygous mother, but the father's phenotype was not provided (Brison et al., 2012). However, the variant has also been observed in the homozygous state at GeneDx in an individual whose phenotype did not match a HOXD13 presentation. The variant is observed in 3/1714 (0.175%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). G11A is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Functional studies have shown that G11A has no effect on DNA binding, transactivation, or localization; however, it speeds protein degradation and led to skeletal abnormalities in chick embryos (Brison et al., 2012). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
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Synpolydactyly type 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at