5-135370028-G-A

Variant names:

• chr5-135370028-G-A
• rs116188576
• NM_138610.3:c.279+8C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_138610.3(MACROH2A1):​c.279+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,554,356 control chromosomes in the GnomAD database, including 49 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 0.0090 (19 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (30 hom.)
• Consequence: MACROH2A1 NM_138610.3 splice_region, intron
• Scores: Splicing: ADA: 0.00008408
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-135370028-G-A is Benign according to our data. Variant chr5-135370028-G-A is described in ClinVar as [Benign]. Clinvar id is 785137.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00899 (1369/152324) while in subpopulation AFR AF = 0.0316 (1313/41556). AF 95% confidence interval is 0.0302. There are 19 homozygotes in GnomAd4. There are 661 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1369 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACROH2A1	NM_138610.3	c.279+8C>T		splice_region_variant, intron_variant	Intron 3 of 8	ENST00000511689.6	NP_613258.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACROH2A1	ENST00000511689.6	c.279+8C>T		splice_region_variant, intron_variant	Intron 3 of 8	1	NM_138610.3	ENSP00000423563.1

Frequencies

GnomAD3 genomes AF: 0.00898 AC: 1367 AN: 152206 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00238 AC: 594 AN: 249672 AF XY: 0.00165

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00105 AC: 1469 AN: 1402032 Hom.: 30 Cov.: 26 AF XY: 0.000953 AC XY: 668 AN XY: 700912

African (AFR) AF: 0.0361 AC: 1166 AN: 32302

American (AMR) AF: 0.00139 AC: 62 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25744

East Asian (EAS) AF: 0.000254 AC: 10 AN: 39438

South Asian (SAS) AF: 0.0000589 AC: 5 AN: 84822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5644

European-Non Finnish (NFE) AF: 0.000110 AC: 116 AN: 1057876

Other (OTH) AF: 0.00173 AC: 101 AN: 58366

GnomAD4 genome AF: 0.00899 AC: 1369 AN: 152324 Hom.: 19 Cov.: 33 AF XY: 0.00887 AC XY: 661 AN XY: 74494

African (AFR) AF: 0.0316 AC: 1313 AN: 41556

American (AMR) AF: 0.00176 AC: 27 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68036

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00628 Hom.: 6

Bravo AF: 0.0101

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.72
DANN	Benign	0.63
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000084
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

Other links and lift over

dbSNP: rs116188576; hg19: chr5-134705718;