12-121804799-C-T

Variant names:

• chr12-121804799-C-T
• rs12814488
• NM_001353345.2:c.62C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001353345.2(SETD1B):​c.62C>T​(p.Ser21Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD1B NM_001353345.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.34
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41638738).

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.62C>T	p.Ser21Leu	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.62C>T	p.Ser21Leu	missense	Exon 2 of 17	ENSP00000474253.1	Q9UPS6-1
	SETD1B	ENST00000619791.1	TSL:1	c.62C>T	p.Ser21Leu	missense	Exon 1 of 16	ENSP00000481531.1	Q9UPS6-1
	SETD1B	ENST00000542440.5	TSL:5	c.62C>T	p.Ser21Leu	missense	Exon 2 of 18	ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.1	L
PhyloP100		4.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.27
MutPred		0.30		Loss of loop (P = 9e-04)
MVP		0.82
MPC		2.4
ClinPred		0.97	D
GERP RS		2.6
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.60
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12814488; hg19: chr12-122242705;