1-150961124-C-T

Position:

• chr1-150961124-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.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. 13/20 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29

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]

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]

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=0.0023070574).
• 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_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1619 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB1	NM_001366418.1	c.3065C>T	p.Ala1022Val	missense_variant	16/22	ENST00000692827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB1	ENST00000692827.1	c.3065C>T	p.Ala1022Val	missense_variant	16/22		NM_001366418.1	A1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1615 AN: 152116 Hom.: 28 Cov.: 31

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

GnomAD3 exomes AF: 0.00773 AC: 1942 AN: 251266 Hom.: 40 AF XY: 0.00888 AC XY: 1207 AN XY: 135854

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 SAS exome AF: 0.0366

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.: 33 AF XY: 0.00448 AC XY: 3255 AN XY: 727204

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.00348

Gnomad4 SAS exome AF: 0.0351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000303

Gnomad4 OTH exome AF: 0.00616

GnomAD4 genome AF: 0.0106 AC: 1619 AN: 152232 Hom.: 28 Cov.: 31 AF XY: 0.0113 AC XY: 843 AN XY: 74424

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.00563

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00812

Gnomad4 SAS AF: 0.0380

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00246 Hom.: 5

Bravo AF: 0.0109

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0234 AC: 103

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00845 AC: 1026

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00107

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	0.083
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
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	T
GERP RS		3.0
Varity_R		0.046
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs150892641; hg19: chr1-150933600;