1-150950463-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 Benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 48 hom. )

Consequence

SETDB1
NM_001366418.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.960

Publications

13 publications found

Variant links:

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]

SETDB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETDB1	NM_001366418.1 link	c.1589C>T	p.Pro530Leu	missense_variant	Exon 13 of 22	ENST00000692827.1	NP_001353347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETDB1	ENST00000692827.1 link	c.1589C>T	p.Pro530Leu	missense_variant	Exon 13 of 22		NM_001366418.1	ENSP00000509425.1		A0A8I5KT93

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

285

AN:

152142

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00328

AC XY:

2351

AN XY:

715788

show subpopulations

African (AFR)

AF:

0.000244

AC:

AN:

32750

American (AMR)

AF:

0.000725

AC:

AN:

41400

Ashkenazi Jewish (ASJ)

AF:

0.0000413

AC:

AN:

24234

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39556

South Asian (SAS)

AF:

0.0217

AC:

1811

AN:

83528

European-Finnish (FIN)

AF:

0.000286

AC:

AN:

52538

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.00146

AC:

1611

AN:

1102286

Other (OTH)

AF:

0.00335

AC:

199

AN:

59390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

201

402

604

805

1006

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00187

AC:

285

AN:

152260

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41544

American (AMR)

AF:

0.000916

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0226

AC:

109

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00187

AC:

127

AN:

68010

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00188

Hom.:

Bravo

AF:

0.00134

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00413

AC:

501

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

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

LIST_S2

Benign

0.76

T;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.55

N;.;N;.

PhyloP100

0.96

PrimateAI

Uncertain

0.49

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

GERP RS

4.0

Varity_R

0.041

gMVP

0.45

Mutation Taster

=97/3

polymorphism

(source)

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

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1-150950463-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over