dbSNP rs138537619: MACROH2A1:p.Thr178Thr (chr5-135360551-T-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_138610.3(MACROH2A1):c.534A>G(p.Thr178Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,614,096 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0034 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 37 hom. )

Consequence

MACROH2A1
NM_138610.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.197

Publications

2 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 Gene-Disease associations (from GenCC):

brachydactyly-elbow wrist dysplasia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MACROH2A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 5-135360551-T-C is Benign according to our data. Variant chr5-135360551-T-C is described in ClinVar as [Benign]. Clinvar id is 799411.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.197 with no splicing effect.

BS2

High AC in GnomAd4 at 517 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACROH2A1	NM_138610.3 link	c.534A>G	p.Thr178Thr	synonymous_variant	Exon 5 of 9	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.534A>G	p.Thr178Thr	synonymous_variant	Exon 5 of 9	1	NM_138610.3	ENSP00000423563.1		O75367-1

Frequencies

GnomAD3 genomes

AF:

0.00340

AC:

517

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0415

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000999

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00409

AC:

1028

AN:

251292

AF XY:

0.00415

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0386

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00176

AC:

2578

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

1261

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0387

AC:

2067

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000343

AC:

381

AN:

1111960

Other (OTH)

AF:

0.00215

AC:

130

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

131

262

394

525

656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00339

AC:

517

AN:

152288

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

374

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41546

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0415

AC:

441

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.000257

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 09, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

4.4

(source)

DANN

Benign

0.58

PhyloP100

-0.20

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism

(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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rs138537619

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over