1-150949438-C-T

Position:

• chr1-150949438-C-T

Variant summary

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

The NM_001366418.1(SETDB1):​c.1496C>T​(p.Ser499Phe) 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: 32)
• Consequence: SETDB1 NM_001366418.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.14

Genes affected

SETDB1 (HGNC:10761): (SET domain bifurcated histone lysine methyltransferase 1) This gene encodes a histone methyltransferase which regulates histone methylation, gene silencing, and transcriptional repression. This gene has been identified as a target for treatment in Huntington Disease, given that gene silencing and transcription dysfunction likely play a role in the disease pathogenesis. Alternatively spliced transcript variants of this gene have been described.[provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETDB1	NM_001366418.1	c.1496C>T	p.Ser499Phe	missense_variant	12/22	ENST00000692827.1	NP_001353347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETDB1	ENST00000692827.1	c.1496C>T	p.Ser499Phe	missense_variant	12/22		NM_001366418.1	ENSP00000509425	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 15, 2024

The c.1493C>T (p.S498F) alteration is located in exon 12 (coding exon 11) of the SETDB1 gene. This alteration results from a C to T substitution at nucleotide position 1493, causing the serine (S) at amino acid position 498 to be replaced by a phenylalanine (F). 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.9	L;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.049	D;D;D;D
Sift4G	Uncertain	0.048	D;D;D;D
Polyphen		0.99	D;D;D;P
Vest4		0.48
MutPred		0.28		Loss of phosphorylation at S498 (P = 0.0028);.;Loss of phosphorylation at S498 (P = 0.0028);Loss of phosphorylation at S498 (P = 0.0028);
MVP		0.74
MPC		1.6
ClinPred		0.90	D
GERP RS		4.9
Varity_R		0.21
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-150921914;