chr5-135388967-C-A

Position:

• chr5-135388967-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_138610.3(MACROH2A1):​c.127G>T​(p.Val43Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: MACROH2A1 NM_138610.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MACROH2A1. . Gene score misZ 3.3004 (greater than the threshold 3.09). Trascript score misZ 3.8574 (greater than threshold 3.09). GenCC has associacion of gene with brachydactyly-elbow wrist dysplasia syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36599642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACROH2A1	NM_138610.3	c.127G>T	p.Val43Leu	missense_variant	2/9	ENST00000511689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACROH2A1	ENST00000511689.6	c.127G>T	p.Val43Leu	missense_variant	2/9	1	NM_138610.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461082 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726882

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: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.127G>T (p.V43L) alteration is located in exon 2 (coding exon 1) of the H2AFY gene. This alteration results from a G to T substitution at nucleotide position 127, causing the valine (V) at amino acid position 43 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.7	L;L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.015	D;D;D;T;D
Sift4G	Uncertain	0.035	D;D;D;D;D
Polyphen		0.57	P;P;D;P;P
Vest4		0.57
MutPred		0.29		Loss of MoRF binding (P = 0.1076);Loss of MoRF binding (P = 0.1076);Loss of MoRF binding (P = 0.1076);Loss of MoRF binding (P = 0.1076);Loss of MoRF binding (P = 0.1076);
MVP		0.55
MPC		2.7
ClinPred		0.89	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs1766814924; hg19: chr5-134724657;