1-149887876-T-C

Variant names:

• chr1-149887876-T-C
• NM_175065.3:c.41A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_175065.3(H2AC21):​c.41A>G​(p.Lys14Arg) variant causes a missense change. 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: 32)
• Consequence: H2AC21 NM_175065.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.15

Genes affected

H2AC21 (HGNC:20508): (H2A clustered histone 21) 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]

BOLA1 (HGNC:24263): (bolA family member 1) Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue N6-(beta-hydroxybutyryl)lysine; alternate (size 0) in uniprot entity H2A2B_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33377624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
H2AC21	NM_175065.3	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 1	ENST00000331128.6	NP_778235.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
H2AC21	ENST00000331128.6	c.41A>G	p.Lys14Arg	missense_variant	Exon 1 of 1	6	NM_175065.3	ENSP00000332790.4
BOLA1	ENST00000369153.2	c.-678T>C		upstream_gene_variant		3		ENSP00000358149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41A>G (p.K14R) alteration is located in exon 1 (coding exon 1) of the HIST2H2AB gene. This alteration results from a A to G substitution at nucleotide position 41, causing the lysine (K) at amino acid position 14 to be replaced by an arginine (R). 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	Benign	0.15
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.034	D
Sift4G	Uncertain	0.060	T
Polyphen		0.82	P
Vest4		0.36
MutPred		0.23		Gain of methylation at K14 (P = 0.0276);
MVP		0.71
MPC		0.80
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.58
gMVP		0.44

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: chr1-149859426;