1-228457766-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_033445.3(H2AC25):c.52C>T(p.Arg18Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,598 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: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

H2AC25
NM_033445.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

Variant links:

Genes affected

H2AC25 (HGNC:20507): (H2A clustered histone 25) Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H2A family. Transcripts from this gene contain a palindromic termination element. [provided by RefSeq, Aug 2015]

H2AC25 links:

ENSG00000231563 (HGNC:):

ENSG00000231563 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2AC25	NM_033445.3 link	c.52C>T	p.Arg18Cys	missense_variant	Exon 1 of 1	ENST00000689584.1	NP_254280.1	Q7L7L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
H2AC25	ENST00000689584.1 link	c.52C>T	p.Arg18Cys	missense_variant	Exon 1 of 1		NM_033445.3	ENSP00000508783.1	Q7L7L0
H2AC25	ENST00000366695.3 link	c.52C>T	p.Arg18Cys	missense_variant	Exon 1 of 1	6		ENSP00000355656.2	Q7L7L0
H2AC25	ENST00000691624.1 link	n.52C>T		non_coding_transcript_exon_variant	Exon 1 of 3			ENSP00000510421.1	Q7L7L0
ENSG00000231563	ENST00000730655.1 link	n.303-237G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000410

AC:

AN:

243840

AF XY:

0.00000750

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000547

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1458598

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33364

American (AMR)

AF:

0.00

AC:

AN:

44492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1110410

Other (OTH)

AF:

0.00

AC:

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.52C>T (p.R18C) alteration is located in exon 1 (coding exon 1) of the HIST3H2A gene. This alteration results from a C to T substitution at nucleotide position 52, causing the arginine (R) at amino acid position 18 to be replaced by a cysteine (C). 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

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.79

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.28

MutationAssessor

Pathogenic

3.4

PhyloP100

7.4

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-6.1

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.055

Polyphen

1.0

Vest4

0.84

MutPred

0.57

Gain of catalytic residue at S20 (P = 0.0249);

MVP

0.87

MPC

1.3

ClinPred

1.0

GERP RS

3.1

PromoterAI

0.040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.62

gMVP

0.67

Mutation Taster

=92/8

polymorphism

(source)

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

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1-228457766-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over