rs143224912

Variant names:

• chr1-150950463-C-T
• rs143224912
• NM_001366418.1:c.1589C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-150950463-C-T
• chr1-150950463-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001366418.1(SETDB1):​c.1589C>T​(p.Pro530Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,593,386 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (48 hom.)
• Consequence: SETDB1 NM_001366418.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.960
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036318898).
• BP6: Variant 1-150950463-C-T is Benign according to our data. Variant chr1-150950463-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 773152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00187 (285/152260) while in subpopulation SAS AF = 0.0226 (109/4820). AF 95% confidence interval is 0.0192. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 285 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.1589C>T	p.Pro530Leu	missense	Exon 13 of 22	NP_001353347.1	A0A8I5KT93
	SETDB1	NM_001366417.1		c.1589C>T	p.Pro530Leu	missense	Exon 13 of 22	NP_001353346.1	A0A8I5KT93
	SETDB1	NM_001393958.1		c.1589C>T	p.Pro530Leu	missense	Exon 13 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.1589C>T	p.Pro530Leu	missense	Exon 13 of 22	ENSP00000509425.1	A0A8I5KT93
	SETDB1	ENST00000271640.9	TSL:1	c.1586C>T	p.Pro529Leu	missense	Exon 13 of 22	ENSP00000271640.5	Q15047-1
	SETDB1	ENST00000368969.8	TSL:1	c.1586C>T	p.Pro529Leu	missense	Exon 13 of 22	ENSP00000357965.4	Q15047-3

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00379 AC: 886 AN: 233482 AF XY: 0.00499

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.000570

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00323

GnomAD4 exome AF: 0.00260 AC: 3750 AN: 1441126 Hom.: 48 Cov.: 32 AF XY: 0.00328 AC XY: 2351 AN XY: 715788

African (AFR) AF: 0.000244 AC: 8 AN: 32750

American (AMR) AF: 0.000725 AC: 30 AN: 41400

Ashkenazi Jewish (ASJ) AF: 0.0000413 AC: 1 AN: 24234

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39556

South Asian (SAS) AF: 0.0217 AC: 1811 AN: 83528

European-Finnish (FIN) AF: 0.000286 AC: 15 AN: 52538

Middle Eastern (MID) AF: 0.0136 AC: 74 AN: 5444

European-Non Finnish (NFE) AF: 0.00146 AC: 1611 AN: 1102286

Other (OTH) AF: 0.00335 AC: 199 AN: 59390

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152260 Hom.: 1 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74440

African (AFR) AF: 0.000337 AC: 14 AN: 41544

American (AMR) AF: 0.000916 AC: 14 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0226 AC: 109 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00187 AC: 127 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00188 Hom.: 4

Bravo AF: 0.00134

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00413 AC: 501

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.75
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.96
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.079
Sift	Benign	0.26	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.60
MPC		0.63
ClinPred		0.0060	T
GERP RS		4.0
Varity_R		0.041
gMVP		0.45
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs143224912; hg19: chr1-150922939; COSMIC: COSV54982914;