NM_018649.3:c.689-98A>G

Variant names:

• chr10-70100110-A-G
• rs3750769
• NM_018649.3:c.689-98A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018649.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACROH2A2	NM_018649.3	MANE Select	c.689-98A>G		intron	N/A	NP_061119.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACROH2A2	ENST00000373255.9	TSL:1 MANE Select	c.689-98A>G		intron	N/A	ENSP00000362352.3
	AIFM2	ENST00000373248.5	TSL:1	c.*34-491T>C		intron	N/A	ENSP00000362345.1
	MACROH2A2	ENST00000678214.1		n.1464A>G		non_coding_transcript_exon	Exon 1 of 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

African (AFR) AF: 0.00529 AC: 69 AN: 13054

American (AMR) AF: 0.143 AC: 2915 AN: 20324

Ashkenazi Jewish (ASJ) AF: 0.0209 AC: 309 AN: 14758

East Asian (EAS) AF: 0.253 AC: 7545 AN: 29764

South Asian (SAS) AF: 0.0311 AC: 1282 AN: 41286

European-Finnish (FIN) AF: 0.0266 AC: 1126 AN: 42336

Middle Eastern (MID) AF: 0.00986 AC: 36 AN: 3650

European-Non Finnish (NFE) AF: 0.0104 AC: 3060 AN: 294138

Other (OTH) AF: 0.0348 AC: 928 AN: 26694

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

African (AFR) AF: 0.00596 AC: 248 AN: 41586

American (AMR) AF: 0.113 AC: 1723 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.234 AC: 1214 AN: 5184

South Asian (SAS) AF: 0.0412 AC: 199 AN: 4828

European-Finnish (FIN) AF: 0.0270 AC: 287 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0121 AC: 825 AN: 68022

Other (OTH) AF: 0.0331 AC: 70 AN: 2114

Alfa AF: 0.0333 Hom.: 137

Bravo AF: 0.0362

Asia WGS AF: 0.130 AC: 449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.22
DANN	Benign	0.44
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3750769; hg19: chr10-71859866;