13-49460127-A-T

Position:

• chr13-49460127-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001160308.3(SETDB2):​c.37A>T​(p.Met13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21824074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETDB2	NM_001160308.3	c.37A>T	p.Met13Leu	missense_variant	3/14	ENST00000611815.2	NP_001153780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETDB2	ENST00000611815.2	c.37A>T	p.Met13Leu	missense_variant	3/14	5	NM_001160308.3	ENSP00000482240.2
SETDB2	ENST00000354234.8	c.37A>T	p.Met13Leu	missense_variant	3/15	1		ENSP00000346175.5
SETDB2	ENST00000317257.12	c.37A>T	p.Met13Leu	missense_variant	2/13	1		ENSP00000326477.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Aug 20, 2024

The c.37A>T (p.M13L) alteration is located in exon 3 (coding exon 2) of the SETDB2 gene. This alteration results from a A to T substitution at nucleotide position 37, causing the methionine (M) at amino acid position 13 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	Benign	0.12
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.043	T;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.2	M;.;M;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.0	N;N;N;.
REVEL	Benign	0.19
Sift	Benign	0.15	T;T;T;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.71	P;.;P;.
Vest4		0.27
MutPred		0.32		Gain of catalytic residue at A8 (P = 0.0271);Gain of catalytic residue at A8 (P = 0.0271);Gain of catalytic residue at A8 (P = 0.0271);Gain of catalytic residue at A8 (P = 0.0271);
MVP		0.59
MPC		0.22
ClinPred		0.55	D
GERP RS		5.5
Varity_R		0.17
gMVP		0.084

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: chr13-50034263;