13-49482939-T-G

Variant summary

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

The NM_001160308.3(SETDB2):c.1359T>G(p.Ser453Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,611,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.124

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=0.117820024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB2	NM_001160308.3	c.1359T>G	p.Ser453Arg	missense_variant	9/14	ENST00000611815.2
SETDB2-PHF11	NR_135324.2	n.2450T>G		non_coding_transcript_exon_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB2	ENST00000611815.2	c.1359T>G	p.Ser453Arg	missense_variant	9/14	5	NM_001160308.3	P1
SETDB2	ENST00000354234.8	c.1395T>G	p.Ser465Arg	missense_variant	10/15	1
SETDB2	ENST00000317257.12	c.1359T>G	p.Ser453Arg	missense_variant	8/13	1		P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250002 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135166

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459310 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725854

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74380

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000416

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

Jan 05, 2022

The c.1395T>G (p.S465R) alteration is located in exon 10 (coding exon 9) of the SETDB2 gene. This alteration results from a T to G substitution at nucleotide position 1395, causing the serine (S) at amino acid position 465 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	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	7.9
Dann	Uncertain	0.98
DEOGEN2	Benign	0.037	T;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
REVEL	Benign	0.24
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.95	P;.;P;.
Vest4		0.12
MutPred		0.45		Gain of catalytic residue at P461 (P = 0);.;.;Gain of catalytic residue at P461 (P = 0);
MVP		0.54
MPC		0.30
ClinPred		0.043	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.21

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: rs1453290331; hg19: chr13-50057075;