Genetic Variant MACROH2A1:c.779-123G>A (chr5-135343557-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.23

Publications

8 publications found

Variant links:

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 links:

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

PITX1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MACROH2A1	NM_138610.3 link	c.779-123G>A		intron_variant	Intron 7 of 8	ENST00000511689.6	NP_613258.2	O75367-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACROH2A1	ENST00000511689.6 link	c.779-123G>A		intron_variant	Intron 7 of 8	1	NM_138610.3	ENSP00000423563.1		O75367-1

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42320

AN:

152014

Hom.:

7793

Cov.:

show subpopulations

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.:

AF XY:

0.190

AC XY:

119786

AN XY:

630826

show subpopulations

African (AFR)

AF:

0.533

AC:

15771

AN:

29586

American (AMR)

AF:

0.277

AC:

9745

AN:

35240

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

3866

AN:

20952

East Asian (EAS)

AF:

0.184

AC:

6923

AN:

37594

South Asian (SAS)

AF:

0.218

AC:

15484

AN:

71186

European-Finnish (FIN)

AF:

0.126

AC:

4368

AN:

34724

Middle Eastern (MID)

AF:

0.175

AC:

769

AN:

4390

European-Non Finnish (NFE)

AF:

0.178

AC:

176387

AN:

989678

Other (OTH)

AF:

0.203

AC:

10890

AN:

53676

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

9564

19128

28692

38256

47820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6522

13044

19566

26088

32610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.279

AC:

42424

AN:

152134

Hom.:

7831

Cov.:

AF XY:

0.276

AC XY:

20552

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.527

AC:

21865

AN:

41474

American (AMR)

AF:

0.263

AC:

4023

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.201

AC:

698

AN:

3468

East Asian (EAS)

AF:

0.186

AC:

964

AN:

5174

South Asian (SAS)

AF:

0.224

AC:

1078

AN:

4818

European-Finnish (FIN)

AF:

0.118

AC:

1252

AN:

10614

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.172

AC:

11669

AN:

67984

Other (OTH)

AF:

0.250

AC:

526

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1409

2818

4227

5636

7045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.211

Hom.:

13931

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

(source)

DANN

Benign

0.48

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over