rs3776203

Variant names:

• chr5-135373075-C-T
• rs3776203
• NM_138610.3:c.173-2933G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138610.3(MACROH2A1):​c.173-2933G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0987 in 152,232 control chromosomes in the GnomAD database, including 896 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 0.099 (896 hom., cov: 33)
• Consequence: MACROH2A1 NM_138610.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 4 publications found

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]

MACROH2A1 Gene-Disease associations (from GenCC):

• brachydactyly-elbow wrist dysplasia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138610.3. 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
	MACROH2A1	NM_138610.3	MANE Select	c.173-2933G>A		intron	N/A	NP_613258.2
	MACROH2A1	NM_001400401.1		c.173-2933G>A		intron	N/A	NP_001387330.1
	MACROH2A1	NM_001400402.1		c.173-2933G>A		intron	N/A	NP_001387331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACROH2A1	ENST00000511689.6	TSL:1 MANE Select	c.173-2933G>A		intron	N/A	ENSP00000423563.1
	MACROH2A1	ENST00000510038.1	TSL:1	c.173-2933G>A		intron	N/A	ENSP00000424971.1
	MACROH2A1	ENST00000304332.8	TSL:1	c.173-2933G>A		intron	N/A	ENSP00000302572.4

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15027 AN: 152114 Hom.: 894 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0793

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.0987 AC: 15029 AN: 152232 Hom.: 896 Cov.: 33 AF XY: 0.0998 AC XY: 7431 AN XY: 74438

African (AFR) AF: 0.0395 AC: 1641 AN: 41550

American (AMR) AF: 0.126 AC: 1929 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3470

East Asian (EAS) AF: 0.113 AC: 584 AN: 5174

South Asian (SAS) AF: 0.165 AC: 794 AN: 4826

European-Finnish (FIN) AF: 0.0793 AC: 841 AN: 10610

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8358 AN: 68002

Other (OTH) AF: 0.109 AC: 231 AN: 2112

Alfa AF: 0.116 Hom.: 1693

Bravo AF: 0.0976

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3776203; hg19: chr5-134708765;