chr6-26225260-G-A

Variant names:

• chr6-26225260-G-A
• NM_003532.3:c.106G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003532.3(H3C6):​c.106G>A​(p.Val36Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: H3C6 NM_003532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

Genes affected

H3C6 (HGNC:4769): (H3 clustered histone 6) 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]

ENSG00000291336 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35417348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3C6	NM_003532.3	c.106G>A	p.Val36Met	missense_variant	Exon 1 of 1	ENST00000614911.3	NP_003523.1
H3C6	NM_001381999.1	c.106G>A	p.Val36Met	missense_variant	Exon 2 of 2		NP_001368928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H3C6	ENST00000614911.3	c.106G>A	p.Val36Met	missense_variant	Exon 1 of 1	6	NM_003532.3	ENSP00000482271.1
H3C6	ENST00000634733.1	c.106G>A	p.Val36Met	missense_variant	Exon 2 of 2	1		ENSP00000489282.1
ENSG00000291336	ENST00000707189.1	n.999+101089G>A		intron_variant	Intron 1 of 1
ENSG00000291338	ENST00000707191.1	n.1000+67139G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.106G>A (p.V36M) alteration is located in exon 1 (coding exon 1) of the HIST1H3E gene. This alteration results from a G to A substitution at nucleotide position 106, causing the valine (V) at amino acid position 36 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	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.88
Eigen	Benign	0.18
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
Sift4G	Benign	0.067	T;T
Vest4		0.49
MVP		0.12
ClinPred		0.70	D
GERP RS		3.6
PromoterAI		0.030	Neutral
gMVP		0.40
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr6-26225488; COSMIC: COSV100839026;