rs773794483

Variant names:

• chr12-121804760-A-C
• rs773794483
• NM_001353345.2:c.23A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-121804760-A-C
• chr12-121804760-A-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001353345.2(SETD1B):​c.23A>C​(p.His8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,371,206 control chromosomes in the GnomAD database, including 13 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H8N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (8 hom.)
• Consequence: SETD1B NM_001353345.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.403
• Publications: 3 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):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with seizures and language delay

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00844124).
• BP6: Variant 12-121804760-A-C is Benign according to our data. Variant chr12-121804760-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2643415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.23A>C	p.His8Pro	missense	Exon 2 of 17	NP_001340274.1	Q9UPS6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1B	ENST00000604567.6	TSL:5 MANE Select	c.23A>C	p.His8Pro	missense	Exon 2 of 17	ENSP00000474253.1	Q9UPS6-1
	SETD1B	ENST00000619791.1	TSL:1	c.23A>C	p.His8Pro	missense	Exon 1 of 16	ENSP00000481531.1	Q9UPS6-1
	SETD1B	ENST00000542440.5	TSL:5	c.23A>C	p.His8Pro	missense	Exon 2 of 18	ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 804 AN: 143024 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00967

Gnomad AMI AF: 0.00117

Gnomad AMR AF: 0.00363

Gnomad ASJ AF: 0.00563

Gnomad EAS AF: 0.000430

Gnomad SAS AF: 0.00512

Gnomad FIN AF: 0.00432

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00749

GnomAD2 exomes AF: 0.00276 AC: 397 AN: 143808 AF XY: 0.00291

Gnomad AFR exome AF: 0.00640

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00430

Gnomad EAS exome AF: 0.000500

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00476

GnomAD4 exome AF: 0.00386 AC: 4746 AN: 1228090 Hom.: 8 Cov.: 34 AF XY: 0.00399 AC XY: 2435 AN XY: 609738

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00918 AC: 249 AN: 27134

American (AMR) AF: 0.00295 AC: 92 AN: 31150

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 104 AN: 21380

East Asian (EAS) AF: 0.000277 AC: 8 AN: 28848

South Asian (SAS) AF: 0.00384 AC: 288 AN: 74952

European-Finnish (FIN) AF: 0.00338 AC: 134 AN: 39658

Middle Eastern (MID) AF: 0.00897 AC: 42 AN: 4680

European-Non Finnish (NFE) AF: 0.00377 AC: 3586 AN: 950434

Other (OTH) AF: 0.00487 AC: 243 AN: 49854

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00560 AC: 801 AN: 143116 Hom.: 5 Cov.: 31 AF XY: 0.00542 AC XY: 378 AN XY: 69746

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00959 AC: 370 AN: 38562

American (AMR) AF: 0.00362 AC: 53 AN: 14628

Ashkenazi Jewish (ASJ) AF: 0.00563 AC: 19 AN: 3374

East Asian (EAS) AF: 0.000431 AC: 2 AN: 4638

South Asian (SAS) AF: 0.00513 AC: 22 AN: 4290

European-Finnish (FIN) AF: 0.00432 AC: 42 AN: 9722

Middle Eastern (MID) AF: 0.0176 AC: 5 AN: 284

European-Non Finnish (NFE) AF: 0.00420 AC: 272 AN: 64746

Other (OTH) AF: 0.00743 AC: 15 AN: 2020

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00301 Hom.: 1

ExAC AF: 0.000491 AC: 11

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.0081	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.0084	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.40
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.013	D
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.61
MPC		2.8
ClinPred		0.021	T
GERP RS		1.4
PromoterAI		-0.064	Neutral
Varity_R		0.31
gMVP		0.57
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs773794483; hg19: chr12-122242666; COSMIC: COSV57349138; COSMIC: COSV57349138;