6-26104083-C-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_003542.4(H4C3):c.136C>A(p.Arg46Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_003542.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Pathogenic:1
The c.136C>A (p.R46S) alteration is located in exon 1 (coding exon 1) of the HIST1H4C gene. This alteration results from a C to A substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). A different alteration at the same codon in a paralogous gene, H4C5 c.136C>T (p.R46C), has been reported de novo in multiple individuals with features consistent with H4C5-related Tessadori-van Haaften neurodevelopmental syndrome (Tessadori, 2022). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant interferes with the hydrogen bond linking H3 and H4 (Davey, 2002; Tessadori, 2022). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.