rs142533394

Variant names:

• chr1-150942901-A-G
• rs142533394
• NM_001366418.1:c.723A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001366418.1(SETDB1):​c.723A>G​(p.Leu241Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000987 in 1,614,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: SETDB1 NM_001366418.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0430
• Publications: 1 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-150942901-A-G is Benign according to our data. Variant chr1-150942901-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 724032.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.043 with no splicing effect.
• BS2: High AC in GnomAd4 at 90 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366418.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETDB1	NM_001366418.1	MANE Select	c.723A>G	p.Leu241Leu	synonymous	Exon 7 of 22	NP_001353347.1	A0A8I5KT93
	SETDB1	NM_001366417.1		c.723A>G	p.Leu241Leu	synonymous	Exon 7 of 22	NP_001353346.1	A0A8I5KT93
	SETDB1	NM_001393958.1		c.723A>G	p.Leu241Leu	synonymous	Exon 7 of 22	NP_001380887.1	A0A8I5KT93

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETDB1	ENST00000692827.1	MANE Select	c.723A>G	p.Leu241Leu	synonymous	Exon 7 of 22	ENSP00000509425.1	A0A8I5KT93
	SETDB1	ENST00000271640.9	TSL:1	c.723A>G	p.Leu241Leu	synonymous	Exon 7 of 22	ENSP00000271640.5	Q15047-1
	SETDB1	ENST00000368969.8	TSL:1	c.723A>G	p.Leu241Leu	synonymous	Exon 7 of 22	ENSP00000357965.4	Q15047-3

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000482 AC: 121 AN: 251294 AF XY: 0.000501

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.000801

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00103 AC: 1504 AN: 1461840 Hom.: 1 Cov.: 31 AF XY: 0.000980 AC XY: 713 AN XY: 727230

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00112 AC: 60 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00125 AC: 1387 AN: 1111970

Other (OTH) AF: 0.000662 AC: 40 AN: 60394

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74498

African (AFR) AF: 0.000168 AC: 7 AN: 41586

American (AMR) AF: 0.000392 AC: 6 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000853 Hom.: 0

Bravo AF: 0.000525

EpiCase AF: 0.000981

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.1
DANN	Benign	0.63
PhyloP100		0.043
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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

dbSNP: rs142533394; hg19: chr1-150915377;