1-150941367-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001366418.1(SETDB1):c.486A>C(p.Gln162His) 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. 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: -0.402

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
• PP2: Missense variant where missense usually causes diseases, SETDB1
• BP4: Computational evidence support a benign effect (MetaRNN=0.27689052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB1	NM_001366418.1	c.486A>C	p.Gln162His	missense_variant	5/22	ENST00000692827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB1	ENST00000692827.1	c.486A>C	p.Gln162His	missense_variant	5/22		NM_001366418.1	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Jan 04, 2022

The c.486A>C (p.Q162H) alteration is located in exon 5 (coding exon 4) of the SETDB1 gene. This alteration results from a A to C substitution at nucleotide position 486, causing the glutamine (Q) at amino acid position 162 to be replaced by a histidine (H). 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	0.31
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.073
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.84	T;T;T;T;T;D;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.033	D
MutationTaster	Benign	0.70	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D;N;N;N;N;D;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.99, 1.0, 1.0, 0.99, 1.0	.;D;D;D;D;.;D
Vest4		0.29, 0.27, 0.27, 0.34
MutPred		0.14		Loss of ubiquitination at K159 (P = 0.0503);Loss of ubiquitination at K159 (P = 0.0503);Loss of ubiquitination at K159 (P = 0.0503);Loss of ubiquitination at K159 (P = 0.0503);Loss of ubiquitination at K159 (P = 0.0503);Loss of ubiquitination at K159 (P = 0.0503);Loss of ubiquitination at K159 (P = 0.0503);
MVP		0.93
MPC		0.61
ClinPred		0.94	D
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.55

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: chr1-150913843;