6-26196947-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001376937.1(H3C4):​c.304G>A​(p.Val102Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

H3C4
NM_001376937.1 missense

Scores

2
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75
Variant links:
Genes affected
H3C4 (HGNC:4767): (H3 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. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H3 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
H3C4NM_001376937.1 linkc.304G>A p.Val102Met missense_variant Exon 1 of 1 ENST00000356476.3 NP_001363866.1
H3C4NM_003530.4 linkc.304G>A p.Val102Met missense_variant Exon 2 of 2 NP_003521.2 P68431

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
H3C4ENST00000356476.3 linkc.304G>A p.Val102Met missense_variant Exon 1 of 1 6 NM_001376937.1 ENSP00000366999.2 P68431
ENSG00000282988ENST00000635200 linkc.*195G>A 3_prime_UTR_variant Exon 2 of 2 3 ENSP00000489311.1 A0A0U1RR32

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152250
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251486
Hom.:
0
AF XY:
0.0000147
AC XY:
2
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:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461892
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152250
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jun 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.304G>A (p.V102M) alteration is located in exon 2 (coding exon 1) of the HIST1H3D gene. This alteration results from a G to A substitution at nucleotide position 304, causing the valine (V) at amino acid position 102 to be replaced by a methionine (M). 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
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
26
DANN
Uncertain
1.0
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.91
D
M_CAP
Benign
0.061
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
-0.086
T
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-2.6
D
REVEL
Uncertain
0.55
Sift4G
Uncertain
0.010
D
Vest4
0.91
MVP
0.45
ClinPred
0.98
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs970318085; hg19: chr6-26197175; API