X-48700738-G-A

Position:

• chrX-48700738-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003173.4(SUV39H1):​c.813G>A​(p.Met271Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: SUV39H1 NM_003173.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.98

Genes affected

SUV39H1 (HGNC:11479): (SUV39H1 histone lysine methyltransferase) This gene encodes an evolutionarily-conserved protein containing an N-terminal chromodomain and a C-terminal SET domain. The encoded protein is a histone methyltransferase that trimethylates lysine 9 of histone H3, which results in transcriptional gene silencing. Loss of function of this gene disrupts heterochromatin formation and may cause chromosome instability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ENSG00000232828 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUV39H1	NM_003173.4	c.813G>A	p.Met271Ile	missense_variant	3/6	ENST00000376687.4	NP_003164.1
SUV39H1	NM_001282166.2	c.846G>A	p.Met282Ile	missense_variant	3/6		NP_001269095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUV39H1	ENST00000376687.4	c.813G>A	p.Met271Ile	missense_variant	3/6	1	NM_003173.4	ENSP00000365877.4
SUV39H1	ENST00000337852.10	c.846G>A	p.Met282Ile	missense_variant	3/6	2		ENSP00000337976.6
ENSG00000232828	ENST00000416061.1	n.126-33C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 22

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 08, 2024

The c.813G>A (p.M271I) alteration is located in exon 3 (coding exon 3) of the SUV39H1 gene. This alteration results from a G to A substitution at nucleotide position 813, causing the methionine (M) at amino acid position 271 to be replaced by an isoleucine (I). 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	0.97
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.54	.;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.23	T;T
Sift4G	Benign	0.54	T;T
Polyphen		0.39	.;B
Vest4		0.80
MutPred		0.66		.;Loss of MoRF binding (P = 0.1118);
MVP		0.92
MPC		1.6
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 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: chrX-48559129;