rs149823680

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138610.3(MACROH2A1):​c.1015G>T​(p.Val339Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,138 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MACROH2A1
NM_138610.3 missense

Scores

2
6
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17
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]
PITX1-AS1 (HGNC:48332): (PITX1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24548489).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MACROH2A1NM_138610.3 linkc.1015G>T p.Val339Leu missense_variant Exon 9 of 9 ENST00000511689.6 NP_613258.2 O75367-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MACROH2A1ENST00000511689.6 linkc.1015G>T p.Val339Leu missense_variant Exon 9 of 9 1 NM_138610.3 ENSP00000423563.1 O75367-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461138
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
726944
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Benign
-0.078
T
BayesDel_noAF
Benign
-0.35
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
T;.;.;T;T
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
.;D;D;D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.25
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.79
N;.;.;.;N
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.3
N;N;N;N;N
REVEL
Benign
0.13
Sift
Benign
0.039
D;D;D;T;D
Sift4G
Uncertain
0.030
D;D;D;T;D
Polyphen
0.71
P;P;P;P;P
Vest4
0.36
MutPred
0.33
Gain of catalytic residue at V339 (P = 0.141);.;.;.;Gain of catalytic residue at V339 (P = 0.141);
MVP
0.34
MPC
0.77
ClinPred
0.81
D
GERP RS
5.2
Varity_R
0.56
gMVP
0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-134670770; API