chr1-150930062-C-T

Variant names:

• chr1-150930062-C-T
• NM_001366418.1:c.356C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001366418.1(SETDB1):​c.356C>T​(p.Pro119Leu) 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: 31)
• Consequence: SETDB1 NM_001366418.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.31
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETDB1	NM_001366418.1	c.356C>T	p.Pro119Leu	missense_variant	Exon 3 of 22	ENST00000692827.1	NP_001353347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETDB1	ENST00000692827.1	c.356C>T	p.Pro119Leu	missense_variant	Exon 3 of 22		NM_001366418.1	ENSP00000509425.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.356C>T (p.P119L) alteration is located in exon 3 (coding exon 2) of the SETDB1 gene. This alteration results from a C to T substitution at nucleotide position 356, causing the proline (P) at amino acid position 119 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	0.16
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;.;.;T;.;.;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.9	.;L;.;L;.;L;.;.;.
PhyloP100		5.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.5	D;N;D;D;D;N;D;N;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		0.89, 1.0, 0.99, 0.99	.;P;.;D;D;D;.;D;.
Vest4		0.61, 0.26, 0.53, 0.35
MutPred		0.29		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;
MVP		0.80
MPC		0.63
ClinPred		0.83	D
GERP RS		5.8
Varity_R		0.19
gMVP		0.24
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

hg19: chr1-150902538;