1-150927814-G-A

Variant names:

• chr1-150927814-G-A
• NM_001366418.1:c.100G>A

Variant summary

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

The NM_001366418.1(SETDB1):​c.100G>A​(p.Gly34Ser) 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: 6.49
• 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.100G>A	p.Gly34Ser	missense_variant	Exon 2 of 22	ENST00000692827.1	NP_001353347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETDB1	ENST00000692827.1	c.100G>A	p.Gly34Ser	missense_variant	Exon 2 of 22		NM_001366418.1	ENSP00000509425.1

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

Apr 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100G>A (p.G34S) alteration is located in exon 2 (coding exon 1) of the SETDB1 gene. This alteration results from a G to A substitution at nucleotide position 100, causing the glycine (G) at amino acid position 34 to be replaced by a serine (S). 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	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;.;.;T;.;.;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.1	.;M;.;M;.;M;.;.;.
PhyloP100		6.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.0	D;N;D;N;N;N;D;N;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.022	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;D;D;D;T;D;D;D
Polyphen		1.0	.;D;.;D;D;D;.;D;.
Vest4		0.59, 0.65, 0.63, 0.59
MutPred		0.47		Gain of phosphorylation at G34 (P = 0.027);Gain of phosphorylation at G34 (P = 0.027);Gain of phosphorylation at G34 (P = 0.027);Gain of phosphorylation at G34 (P = 0.027);Gain of phosphorylation at G34 (P = 0.027);Gain of phosphorylation at G34 (P = 0.027);Gain of phosphorylation at G34 (P = 0.027);Gain of phosphorylation at G34 (P = 0.027);.;
MVP		0.81
MPC		1.6
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.42
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

hg19: chr1-150900290;