1-150929964-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001366418.1(SETDB1):c.261-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,612,404 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0085 (80 hom.)
• Consequence: SETDB1 NM_001366418.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009894
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.348

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-150929964-T-C is Benign according to our data. Variant chr1-150929964-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 779065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 904 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB1	NM_001366418.1	c.261-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000692827.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB1	ENST00000692827.1	c.261-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001366418.1	A1

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 904 AN: 152150 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00571 AC: 1426 AN: 249720 Hom.: 12 AF XY: 0.00593 AC XY: 801 AN XY: 135016

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00270

Gnomad FIN exome AF: 0.00389

Gnomad NFE exome AF: 0.00957

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00851 AC: 12421 AN: 1460136 Hom.: 80 Cov.: 30 AF XY: 0.00851 AC XY: 6180 AN XY: 726396

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00260

Gnomad4 ASJ exome AF: 0.00365

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00310

Gnomad4 FIN exome AF: 0.00455

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.00819

GnomAD4 genome AF: 0.00593 AC: 903 AN: 152268 Hom.: 4 Cov.: 31 AF XY: 0.00540 AC XY: 402 AN XY: 74452

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00786 Hom.: 0

Bravo AF: 0.00570

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0108

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SETDB1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	12
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000099
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.010		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: rs138878430; hg19: chr1-150902440;