12-121823550-G-A

Variant names:

• chr12-121823550-G-A
• rs3741593
• NM_001353345.2:c.4971G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001353345.2(SETD1B):​c.4971G>A​(p.Ala1657Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 1,550,642 control chromosomes in the GnomAD database, including 211,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (15220 hom., cov: 30)
  • Exomes 𝑓: 0.52 (196656 hom.)
• Consequence: SETD1B NM_001353345.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.77
• Publications: 18 publications found

Genes affected

SETD1B (HGNC:29187): (SET domain containing 1B, histone lysine methyltransferase) SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4 (Lee et al., 2007 [PubMed 17355966]).[supplied by OMIM, Mar 2008]

SETD1B Gene-Disease associations (from GenCC):

• intellectual developmental disorder with seizures and language delay

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-121823550-G-A is Benign according to our data. Variant chr12-121823550-G-A is described in ClinVar as Benign. ClinVar VariationId is 1284001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353345.2. 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
	SETD1B	NM_001353345.2	MANE Select	c.4971G>A	p.Ala1657Ala	synonymous	Exon 12 of 17	NP_001340274.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1B	ENST00000604567.6	TSL:5 MANE Select	c.4971G>A	p.Ala1657Ala	synonymous	Exon 12 of 17	ENSP00000474253.1
	SETD1B	ENST00000619791.1	TSL:1	c.4971G>A	p.Ala1657Ala	synonymous	Exon 11 of 16	ENSP00000481531.1
	SETD1B	ENST00000542440.5	TSL:5	c.4842G>A	p.Ala1614Ala	synonymous	Exon 13 of 18	ENSP00000442924.1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61719 AN: 151724 Hom.: 15216 Cov.: 30

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.535

Gnomad OTH AF: 0.449

GnomAD2 exomes AF: 0.493 AC: 76576 AN: 155294 AF XY: 0.497

Gnomad AFR exome AF: 0.0866

Gnomad AMR exome AF: 0.462

Gnomad ASJ exome AF: 0.616

Gnomad EAS exome AF: 0.571

Gnomad FIN exome AF: 0.469

Gnomad NFE exome AF: 0.543

Gnomad OTH exome AF: 0.528

GnomAD4 exome AF: 0.524 AC: 733166 AN: 1398800 Hom.: 196656 Cov.: 59 AF XY: 0.524 AC XY: 361266 AN XY: 689908

African (AFR) AF: 0.0862 AC: 2725 AN: 31598

American (AMR) AF: 0.462 AC: 16490 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 15541 AN: 25178

East Asian (EAS) AF: 0.544 AC: 19454 AN: 35730

South Asian (SAS) AF: 0.467 AC: 36988 AN: 79234

European-Finnish (FIN) AF: 0.465 AC: 22712 AN: 48854

Middle Eastern (MID) AF: 0.563 AC: 3207 AN: 5698

European-Non Finnish (NFE) AF: 0.543 AC: 586263 AN: 1078822

Other (OTH) AF: 0.514 AC: 29786 AN: 57984

GnomAD4 genome AF: 0.406 AC: 61714 AN: 151842 Hom.: 15220 Cov.: 30 AF XY: 0.408 AC XY: 30274 AN XY: 74168

African (AFR) AF: 0.106 AC: 4402 AN: 41474

American (AMR) AF: 0.465 AC: 7100 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2140 AN: 3468

East Asian (EAS) AF: 0.556 AC: 2863 AN: 5150

South Asian (SAS) AF: 0.470 AC: 2254 AN: 4800

European-Finnish (FIN) AF: 0.464 AC: 4878 AN: 10524

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.535 AC: 36332 AN: 67852

Other (OTH) AF: 0.453 AC: 958 AN: 2114

Alfa AF: 0.490 Hom.: 18940

Bravo AF: 0.397

Asia WGS AF: 0.499 AC: 1735 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.011
DANN	Benign	0.62
PhyloP100		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3741593; hg19: chr12-122261456; COSMIC: COSV57348987;