5-135343557-C-T

Position:

• chr5-135343557-C-T

Variant summary

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

The NM_138610.3(MACROH2A1):​c.779-123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,429,160 control chromosomes in the GnomAD database, including 33,550 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 0.28 (7831 hom., cov: 33)
  • Exomes 𝑓: 0.19 (25719 hom.)
• Consequence: MACROH2A1 NM_138610.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACROH2A1	NM_138610.3	c.779-123G>A		intron_variant		ENST00000511689.6
PITX1-AS1	NR_161235.1	n.1357C>T		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACROH2A1	ENST00000511689.6	c.779-123G>A		intron_variant		1	NM_138610.3	A1
PITX1-AS1	ENST00000624272.3	n.1351C>T		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42320 AN: 152014 Hom.: 7793 Cov.: 33

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.252

GnomAD4 exome AF: 0.191 AC: 244203 AN: 1277026 Hom.: 25719 Cov.: 19 AF XY: 0.190 AC XY: 119786 AN XY: 630826

Gnomad4 AFR exome AF: 0.533

Gnomad4 AMR exome AF: 0.277

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.279 AC: 42424 AN: 152134 Hom.: 7831 Cov.: 33 AF XY: 0.276 AC XY: 20552 AN XY: 74392

Gnomad4 AFR AF: 0.527

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.250

Alfa AF: 0.188 Hom.: 6164

Bravo AF: 0.299

Asia WGS AF: 0.225 AC: 785 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292011; hg19: chr5-134679247; COSMIC: COSV56898862; COSMIC: COSV56898862;