rs4746946

Positions:

• chr10-70055076-A-G
• chr10-70055076-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018649.3(MACROH2A2):​c.-60+2076A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,068 control chromosomes in the GnomAD database, including 19,147 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19147 hom., cov: 32)
• Consequence: MACROH2A2 NM_018649.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15

Genes affected

MACROH2A2 (HGNC:14453): (macroH2A.2 histone) 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 encodes a replication-independent histone that is a member of the histone H2A family. It replaces conventional H2A histones in a subset of nucleosomes where it represses transcription and may participate in stable X chromosome inactivation. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACROH2A2	NM_018649.3	c.-60+2076A>G		intron_variant		ENST00000373255.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACROH2A2	ENST00000373255.9	c.-60+2076A>G		intron_variant		1	NM_018649.3	P1

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75669 AN: 151950 Hom.: 19120 Cov.: 32

Gnomad AFR AF: 0.522

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.627

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.461

Gnomad OTH AF: 0.498

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75749 AN: 152068 Hom.: 19147 Cov.: 32 AF XY: 0.501 AC XY: 37228 AN XY: 74344

Gnomad4 AFR AF: 0.522

Gnomad4 AMR AF: 0.582

Gnomad4 ASJ AF: 0.449

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.628

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.461

Gnomad4 OTH AF: 0.498

Alfa AF: 0.479 Hom.: 17037

Bravo AF: 0.511

Asia WGS AF: 0.630 AC: 2191 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	19
DANN	Benign	0.63

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: rs4746946; hg19: chr10-71814832;