1-150961124-C-T

Variant names:

• chr1-150961124-C-T
• rs150892641
• NM_001366418.1:c.3065C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29
• Publications: 7 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]

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

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366418.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETDB1	NM_001366418.1	MANE Select	c.3065C>T	p.Ala1022Val	missense	Exon 16 of 22	NP_001353347.1	A0A8I5KT93
	SETDB1	NM_001366417.1		c.3065C>T	p.Ala1022Val	missense	Exon 16 of 22	NP_001353346.1	A0A8I5KT93
	SETDB1	NM_001393958.1		c.3065C>T	p.Ala1022Val	missense	Exon 16 of 22	NP_001380887.1	A0A8I5KT93

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETDB1	ENST00000692827.1	MANE Select	c.3065C>T	p.Ala1022Val	missense	Exon 16 of 22	ENSP00000509425.1	A0A8I5KT93
	SETDB1	ENST00000271640.9	TSL:1	c.3062C>T	p.Ala1021Val	missense	Exon 16 of 22	ENSP00000271640.5	Q15047-1
	SETDB1	ENST00000368969.8	TSL:1	c.3062C>T	p.Ala1021Val	missense	Exon 16 of 22	ENSP00000357965.4	Q15047-3

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

GnomAD2 exomes AF: 0.00773 AC: 1942 AN: 251266 AF XY: 0.00888

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

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: 93 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: 0 AN: 53418

Middle Eastern (MID) AF: 0.00453 AC: 26 AN: 5742

European-Non Finnish (NFE) AF: 0.000303 AC: 337 AN: 1111972

Other (OTH) AF: 0.00616 AC: 372 AN: 60394

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

African (AFR) AF: 0.0300 AC: 1245 AN: 41534

American (AMR) AF: 0.00563 AC: 86 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00812 AC: 42 AN: 5174

South Asian (SAS) AF: 0.0380 AC: 183 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68016

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00303 Hom.: 10

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.12
Sift	Benign	0.056	T
Sift4G	Benign	0.29	T
Polyphen		0.0	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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs150892641; hg19: chr1-150933600; COSMIC: COSV107229346; COSMIC: COSV107229346;