rs138878430

Variant names:

• chr1-150929964-T-C
• rs138878430
• NM_001366418.1:c.261-3T>C

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00009894
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.348
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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 GnomAd4 at 903 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETDB1	NM_001366418.1	c.261-3T>C		splice_region_variant, intron_variant	Intron 2 of 21	ENST00000692827.1	NP_001353347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETDB1	ENST00000692827.1	c.261-3T>C		splice_region_variant, intron_variant	Intron 2 of 21		NM_001366418.1	ENSP00000509425.1

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

GnomAD2 exomes AF: 0.00571 AC: 1426 AN: 249720 AF XY: 0.00593

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 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

African (AFR) AF: 0.00102 AC: 34 AN: 33412

American (AMR) AF: 0.00260 AC: 115 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00365 AC: 95 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00310 AC: 267 AN: 86012

European-Finnish (FIN) AF: 0.00455 AC: 243 AN: 53372

Middle Eastern (MID) AF: 0.00400 AC: 23 AN: 5756

European-Non Finnish (NFE) AF: 0.0100 AC: 11150 AN: 1111280

Other (OTH) AF: 0.00819 AC: 494 AN: 60298

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

African (AFR) AF: 0.00209 AC: 87 AN: 41562

American (AMR) AF: 0.00314 AC: 48 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 688 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00763 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SETDB1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.84
PhyloP100		0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs138878430; hg19: chr1-150902440;