NM_001366418.1:c.3065C>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.3065C>T(p.Ala1022Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,614,036 control chromosomes in the GnomAD database, including 152 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 0.011 ( 28 hom., cov: 31)

Exomes 𝑓: 0.0036 ( 124 hom. )

Consequence

SETDB1
NM_001366418.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.29

Publications

7 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:

CERS2 (HGNC:14076): (ceramide synthase 2) This gene encodes a protein that has sequence similarity to yeast longevity assurance gene 1. Mutation or overexpression of the related gene in yeast has been shown to alter yeast lifespan. The human protein may play a role in the regulation of cell growth. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

CERS2 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=0.0023070574).

BP6

Variant 1-150961124-C-T is Benign according to our data. Variant chr1-150961124-C-T is described in ClinVar as [Benign]. Clinvar id is 710875.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 = 0.0106 (1619/152232) while in subpopulation SAS AF = 0.038 (183/4816). AF 95% confidence interval is 0.0335. There are 28 homozygotes in GnomAd4. There are 843 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1619 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETDB1	NM_001366418.1 link	c.3065C>T	p.Ala1022Val	missense_variant	Exon 16 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.3065C>T	p.Ala1022Val	missense_variant	Exon 16 of 22		NM_001366418.1	ENSP00000509425.1		A0A8I5KT93

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1615

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00810

Gnomad SAS

AF:

0.0384

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00773

AC:

1942

AN:

251266

AF XY:

0.00888

show subpopulations

Gnomad AFR exome

AF:

0.0295

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00658

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000599

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00358

AC:

5237

AN:

1461804

Hom.:

124

Cov.:

AF XY:

0.00448

AC XY:

3255

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.0335

AC:

1121

AN:

33470

American (AMR)

AF:

0.00268

AC:

120

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00356

AC:

AN:

26136

East Asian (EAS)

AF:

0.00348

AC:

138

AN:

39692

South Asian (SAS)

AF:

0.0351

AC:

3030

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00453

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000303

AC:

337

AN:

1111972

Other (OTH)

AF:

0.00616

AC:

372

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

311

623

934

1246

1557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0106

AC:

1619

AN:

152232

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

843

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0300

AC:

1245

AN:

41534

American (AMR)

AF:

0.00563

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00812

AC:

AN:

5174

South Asian (SAS)

AF:

0.0380

AC:

183

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68016

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

156

235

313

391

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00303

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00845

AC:

1026

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.71

T;T;T

MetaRNN

Benign

0.0023

T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.1

L;L;.

PhyloP100

1.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.25

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.056

T;T;D

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.072

MVP

0.39

MPC

0.74

ClinPred

0.0068

GERP RS

3.0

Varity_R

0.046

gMVP

0.30

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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NM_001366418.1:c.3065C>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