1-150950463-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.960

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 Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SETDB1
• 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]. Clinvar id is 773152.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 285 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB1	NM_001366418.1	c.1589C>T	p.Pro530Leu	missense_variant	13/22	ENST00000692827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB1	ENST00000692827.1	c.1589C>T	p.Pro530Leu	missense_variant	13/22		NM_001366418.1	A1

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

GnomAD3 exomes AF: 0.00379 AC: 886 AN: 233482 Hom.: 9 AF XY: 0.00499 AC XY: 630 AN XY: 126286

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 SAS exome AF: 0.0222

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

Gnomad4 AFR exome AF: 0.000244

Gnomad4 AMR exome AF: 0.000725

Gnomad4 ASJ exome AF: 0.0000413

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0217

Gnomad4 FIN exome AF: 0.000286

Gnomad4 NFE exome AF: 0.00146

Gnomad4 OTH exome AF: 0.00335

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

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00184 Hom.: 0

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.55	N;.;N;.
MutationTaster	Benign	0.72	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Benign	0.079
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.0	B;B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs143224912; hg19: chr1-150922939; COSMIC: COSV54982914;