rs6865399

Variant names:

• chr5-135338889-C-G
• rs6865399
• NM_138610.3:c.954-3748G>C

Variant summary

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

The NM_138610.3(MACROH2A1):​c.954-3748G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0922 in 152,236 control chromosomes in the GnomAD database, including 692 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 0.092 (692 hom., cov: 33)
• Consequence: MACROH2A1 NM_138610.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• Publications: 3 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]

PITX1-AS1 (HGNC:48332): (PITX1 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACROH2A1	NM_138610.3	c.954-3748G>C		intron_variant	Intron 8 of 8	ENST00000511689.6	NP_613258.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACROH2A1	ENST00000511689.6	c.954-3748G>C		intron_variant	Intron 8 of 8	1	NM_138610.3	ENSP00000423563.1

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14024 AN: 152118 Hom.: 694 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0957

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.0803

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0773

Gnomad OTH AF: 0.0850

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

GnomAD4 genome AF: 0.0922 AC: 14037 AN: 152236 Hom.: 692 Cov.: 33 AF XY: 0.0907 AC XY: 6754 AN XY: 74432

African (AFR) AF: 0.111 AC: 4616 AN: 41538

American (AMR) AF: 0.115 AC: 1752 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 351 AN: 3470

East Asian (EAS) AF: 0.0953 AC: 494 AN: 5184

South Asian (SAS) AF: 0.0809 AC: 391 AN: 4832

European-Finnish (FIN) AF: 0.0803 AC: 852 AN: 10604

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0773 AC: 5256 AN: 68006

Other (OTH) AF: 0.0841 AC: 178 AN: 2116

Alfa AF: 0.0906 Hom.: 81

Bravo AF: 0.0948

Asia WGS AF: 0.106 AC: 368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.51
PhyloP100		-0.19
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: rs6865399; hg19: chr5-134674579;