1-150962697-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.3272C>T(p.Ala1091Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,614,178 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (33 hom.)
• Consequence: SETDB1 NM_001366418.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.738

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=0.00337106).
• BP6: Variant 1-150962697-C-T is Benign according to our data. Variant chr1-150962697-C-T is described in ClinVar as [Benign]. Clinvar id is 773638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00157 (239/152316) while in subpopulation EAS AF= 0.0366 (190/5186). AF 95% confidence interval is 0.0324. There are 12 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 242 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB1	NM_001366418.1	c.3272C>T	p.Ala1091Val	missense_variant	18/22	ENST00000692827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB1	ENST00000692827.1	c.3272C>T	p.Ala1091Val	missense_variant	18/22		NM_001366418.1	A1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152198 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0369

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00286 AC: 719 AN: 251410 Hom.: 17 AF XY: 0.00258 AC XY: 351 AN XY: 135884

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0361

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000771 AC: 1127 AN: 1461862 Hom.: 33 Cov.: 32 AF XY: 0.000711 AC XY: 517 AN XY: 727236

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0178

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152316 Hom.: 12 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74490

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0366

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00120 Hom.: 4

Bravo AF: 0.00138

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00275 AC: 334

Asia WGS AF: 0.0290 AC: 100 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.091
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.082	T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.074	T;T;D
Sift4G	Benign	0.31	T;T;T
Polyphen		0.085	B;B;B
Vest4		0.49
MVP		0.74
MPC		0.61
ClinPred		0.0094	T
GERP RS		4.2
Varity_R		0.091
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75743857; hg19: chr1-150935173; COSMIC: COSV54992865; COSMIC: COSV54992865;