6-26225536-G-C

Variant names:

• chr6-26225536-G-C
• rs1333188920
• NM_003532.3:c.382G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003532.3(H3C6):​c.382G>C​(p.Ala128Pro) 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 pathogenic 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: 9.92

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H3C6	NM_003532.3	c.382G>C	p.Ala128Pro	missense_variant	Exon 1 of 1	ENST00000614911.3	NP_003523.1
H3C6	NM_001381999.1	c.382G>C	p.Ala128Pro	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.382G>C	p.Ala128Pro	missense_variant	Exon 1 of 1	6	NM_003532.3	ENSP00000482271.1
H3C6	ENST00000634733.1	c.382G>C	p.Ala128Pro	missense_variant	Exon 2 of 2	1		ENSP00000489282.1
ENSG00000291336	ENST00000707189.1	n.999+101365G>C		intron_variant	Intron 1 of 1
ENSG00000291338	ENST00000707191.1	n.1000+67415G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.382G>C (p.A128P) alteration is located in exon 1 (coding exon 1) of the HIST1H3E gene. This alteration results from a G to C substitution at nucleotide position 382, causing the alanine (A) at amino acid position 128 to be replaced by a proline (P). 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	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.15	D
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.0060	D;D
Vest4		0.91
MVP		0.13
ClinPred		0.97	D
GERP RS		3.7
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs1333188920; hg19: chr6-26225764;