chr6-26027091-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_003544.3(H4C2):​c.162G>T​(p.Glu54Asp) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

H4C2
NM_003544.3 missense

Scores

2
6
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.78
Variant links:
Genes affected
H4C2 (HGNC:4789): (H4 clustered histone 2) 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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a chain Histone H4 (size 101) in uniprot entity H4_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_003544.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H4C2NM_003544.3 linkc.162G>T p.Glu54Asp missense_variant Exon 1 of 1 ENST00000377745.5 NP_003535.1 P62805B2R4R0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
H4C2ENST00000377745.5 linkc.162G>T p.Glu54Asp missense_variant Exon 1 of 1 6 NM_003544.3 ENSP00000366974.2 P62805

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251486
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 18, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.162G>T (p.E54D) alteration is located in exon 1 (coding exon 1) of the HIST1H4B gene. This alteration results from a G to T substitution at nucleotide position 162, causing the glutamic acid (E) at amino acid position 54 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.070
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
22
DANN
Uncertain
1.0
Eigen
Benign
0.097
Eigen_PC
Benign
0.083
FATHMM_MKL
Uncertain
0.97
D
M_CAP
Benign
0.026
D
MetaRNN
Pathogenic
0.78
D
MetaSVM
Benign
-0.45
T
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-2.9
D
Sift
Uncertain
0.0050
D
Sift4G
Benign
0.17
T
Vest4
0.87
MVP
0.30
ClinPred
0.95
D
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147907725; hg19: chr6-26027319; API