5-135343347-A-G

Position:

• chr5-135343347-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_138610.3(MACROH2A1):​c.866T>C​(p.Leu289Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L289F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MACROH2A1 NM_138610.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36

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

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACROH2A1	NM_138610.3	c.866T>C	p.Leu289Pro	missense_variant	8/9	ENST00000511689.6
PITX1-AS1	NR_161235.1	n.1147A>G		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACROH2A1	ENST00000511689.6	c.866T>C	p.Leu289Pro	missense_variant	8/9	1	NM_138610.3	A1
PITX1-AS1	ENST00000624272.3	n.1141A>G		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Mar 01, 2023

The c.866T>C (p.L289P) alteration is located in exon 8 (coding exon 7) of the H2AFY gene. This alteration results from a T to C substitution at nucleotide position 866, causing the leucine (L) at amino acid position 289 to be replaced by a proline (P). 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	0.89
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;.;.;T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	.;T;T;T;T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Uncertain	-0.092	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.28	N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.024	B;B;D;B;B
Vest4		0.83
MutPred		0.70		Gain of disorder (P = 0.0227);.;.;.;Gain of disorder (P = 0.0227);
MVP		0.60
MPC		0.94
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.67
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-134679037;