chr5-135335080-C-A

Variant names:

• chr5-135335080-C-A
• rs149823680
• NM_138610.3:c.1015G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V339M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MACROH2A1 NM_138610.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
MACROH2A1	NM_138610.3	c.1015G>T	p.Val339Leu	missense_variant	Exon 9 of 9	ENST00000511689.6	NP_613258.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACROH2A1	ENST00000511689.6	c.1015G>T	p.Val339Leu	missense_variant	Exon 9 of 9	1	NM_138610.3	ENSP00000423563.1

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

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111330

Other (OTH) AF: 0.00 AC: 0 AN: 60372

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
PhyloP100		6.2
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
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs149823680; hg19: chr5-134670770;