rs3750769

Positions:

• chr10-70100110-A-G

Variant summary

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

The NM_018649.3(MACROH2A2):​c.689-98A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 638,328 control chromosomes in the GnomAD database, including 1,654 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 0.030 (310 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1344 hom.)
• Consequence: MACROH2A2 NM_018649.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35

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]

AIFM2 (HGNC:21411): (apoptosis inducing factor mitochondria associated 2) This gene encodes a flavoprotein oxidoreductase that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells. [provided by RefSeq, Nov 2010]

MACROH2A2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACROH2A2	NM_018649.3	c.689-98A>G		intron_variant		ENST00000373255.9	NP_061119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACROH2A2	ENST00000373255.9	c.689-98A>G		intron_variant		1	NM_018649.3	ENSP00000362352.3

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4638 AN: 152206 Hom.: 308 Cov.: 33

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0339

GnomAD4 exome AF: 0.0355 AC: 17270 AN: 486004 Hom.: 1344 AF XY: 0.0343 AC XY: 8729 AN XY: 254302

Gnomad4 AFR exome AF: 0.00529

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.0209

Gnomad4 EAS exome AF: 0.253

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.0266

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.0348

GnomAD4 genome AF: 0.0305 AC: 4639 AN: 152324 Hom.: 310 Cov.: 33 AF XY: 0.0340 AC XY: 2534 AN XY: 74490

Gnomad4 AFR AF: 0.00596

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.0412

Gnomad4 FIN AF: 0.0270

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0354 Hom.: 129

Bravo AF: 0.0362

Asia WGS AF: 0.130 AC: 449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.44

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

LitVar

Other links and lift over

dbSNP: rs3750769; hg19: chr10-71859866;