NM_018649.3:c.780C>T

Variant names:

• chr10-70109034-C-T
• rs74139271
• NM_018649.3:c.780C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_018649.3(MACROH2A2):​c.780C>T​(p.Ala260Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,880 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (24 hom.)
• Consequence: MACROH2A2 NM_018649.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.000007072
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.19

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-70109034-C-T is Benign according to our data. Variant chr10-70109034-C-T is described in ClinVar as [Benign]. Clinvar id is 780867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1648/152290) while in subpopulation AFR AF= 0.0365 (1516/41564). AF 95% confidence interval is 0.0349. There are 22 homozygotes in gnomad4. There are 752 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACROH2A2	NM_018649.3	c.780C>T	p.Ala260Ala	splice_region_variant, synonymous_variant	Exon 8 of 9	ENST00000373255.9	NP_061119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACROH2A2	ENST00000373255.9	c.780C>T	p.Ala260Ala	splice_region_variant, synonymous_variant	Exon 8 of 9	1	NM_018649.3	ENSP00000362352.3

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1645 AN: 152172 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00309 AC: 776 AN: 251336 Hom.: 17 AF XY: 0.00222 AC XY: 302 AN XY: 135820

Gnomad AFR exome AF: 0.0403

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00120 AC: 1756 AN: 1461590 Hom.: 24 Cov.: 32 AF XY: 0.00103 AC XY: 751 AN XY: 727080

Gnomad4 AFR exome AF: 0.0372

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.0108 AC: 1648 AN: 152290 Hom.: 22 Cov.: 32 AF XY: 0.0101 AC XY: 752 AN XY: 74456

Gnomad4 AFR AF: 0.0365

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00154 Hom.: 2

Bravo AF: 0.0125

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0
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: rs74139271; hg19: chr10-71868790; COSMIC: COSV57161203; COSMIC: COSV57161203;