13-49481012-A-G

Position:

• chr13-49481012-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001160308.3(SETDB2):​c.1052A>G​(p.His351Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

Genes affected

SETDB2 (HGNC:20263): (SET domain bifurcated histone lysine methyltransferase 2) This gene encodes a member of a family of proteins that contain a methyl-CpG-binding domain (MBD) and a SET domain and function as histone methyltransferases. This protein is recruited to heterochromatin and plays a role in the regulation of chromosome segregation. This region is commonly deleted in chronic lymphocytic leukemia. Naturally-occuring readthrough transcription occurs from this gene to the downstream PHF11 (PHD finger protein 11) gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

SETDB2-PHF11 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity SETB2_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETDB2	NM_001160308.3	c.1052A>G	p.His351Arg	missense_variant	8/14	ENST00000611815.2	NP_001153780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETDB2	ENST00000611815.2	c.1052A>G	p.His351Arg	missense_variant	8/14	5	NM_001160308.3	ENSP00000482240.2
SETDB2	ENST00000354234.8	c.1088A>G	p.His363Arg	missense_variant	9/15	1		ENSP00000346175.5
SETDB2	ENST00000317257.12	c.1052A>G	p.His351Arg	missense_variant	7/13	1		ENSP00000326477.9

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

Nov 07, 2023

The c.1088A>G (p.H363R) alteration is located in exon 9 (coding exon 8) of the SETDB2 gene. This alteration results from a A to G substitution at nucleotide position 1088, causing the histidine (H) at amino acid position 363 to be replaced by an arginine (R). 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	Benign	0.14
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	0.91	L;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.6	.;D;.;.
REVEL	Uncertain	0.53
Sift	Benign	0.047	.;D;.;.
Sift4G	Uncertain	0.014	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.16
MutPred		0.49		Gain of MoRF binding (P = 0.0075);.;.;Gain of MoRF binding (P = 0.0075);
MVP		0.89
MPC		0.31
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1958465720; hg19: chr13-50055148;