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

Genomes: not found (cov: 32)

Consequence

H4C3
NM_003542.4 missense

Scores

7
7
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.00
Variant links:
Genes affected
H4C3 (HGNC:4787): (H4 clustered histone 3) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H4 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Aug 2015]
H2BC4 (HGNC:4757): (H2B clustered histone 4) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. The protein has antibacterial and antifungal antimicrobial activity. The main transcript variant of this gene is intronless and encodes a replication-dependent histone that is a member of the histone H2B family. This transcript variant lacks a polyA tail but instead contains a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6. [provided by RefSeq, Apr 2020]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a chain Histone H4 (size 101) in uniprot entity H4_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) in NM_003542.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
Variant 6-26104083-C-A is Pathogenic according to our data. Variant chr6-26104083-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2597503.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H4C3NM_003542.4 linkc.136C>A p.Arg46Ser missense_variant Exon 1 of 1 ENST00000377803.4 NP_003533.1 P62805B2R4R0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
H4C3ENST00000377803.4 linkc.136C>A p.Arg46Ser missense_variant Exon 1 of 1 6 NM_003542.4 ENSP00000367034.3 P62805
H2BC4ENST00000707188.1 linkn.*10-13049G>T intron_variant Intron 1 of 2 ENSP00000516775.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Pathogenic:1
Sep 11, 2023
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
0.029
D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-5.9
D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0030
D
Vest4
0.95
MutPred
0.79
Loss of MoRF binding (P = 0.0381);
MVP
0.45
ClinPred
1.0
D
GERP RS
4.6
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-26104311; API