rs1393082

Positions:

• chr5-135371383-C-A

Variant summary

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

The NM_138610.3(MACROH2A1):​c.173-1241G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 152,062 control chromosomes in the GnomAD database, including 21,637 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 0.48 (21637 hom., cov: 33)
• Consequence: MACROH2A1 NM_138610.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.648

Genes affected

MACROH2A1 (HGNC:4740): (macroH2A.1 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 participates in stable X chromosome inactivation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACROH2A1	NM_138610.3	c.173-1241G>T		intron_variant		ENST00000511689.6	NP_613258.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACROH2A1	ENST00000511689.6	c.173-1241G>T		intron_variant		1	NM_138610.3	ENSP00000423563	A1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72315 AN: 151944 Hom.: 21576 Cov.: 33

Gnomad AFR AF: 0.851

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.465

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.477

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

GnomAD4 genome AF: 0.476 AC: 72436 AN: 152062 Hom.: 21637 Cov.: 33 AF XY: 0.471 AC XY: 35033 AN XY: 74336

Gnomad4 AFR AF: 0.851

Gnomad4 AMR AF: 0.421

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.475

Alfa AF: 0.362 Hom.: 12893

Bravo AF: 0.509

Asia WGS AF: 0.454 AC: 1578 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.86
DANN	Benign	0.46

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: rs1393082; hg19: chr5-134707073;