chr12-121804761-C-G

Position:

• chr12-121804761-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001353345.2(SETD1B):​c.24C>G​(p.His8Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD1B NM_001353345.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SETD1B. . Trascript score misZ 3.1492 (greater than threshold 3.09). GenCC has associacion of gene with intellectual developmental disorder with seizures and language delay.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2799996).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.24C>G	p.His8Gln	missense_variant	2/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.24C>G	p.His8Gln	missense_variant	2/17		XP_024304666.1
SETD1B	XM_047428552.1	c.24C>G	p.His8Gln	missense_variant	2/17		XP_047284508.1
SETD1B	XM_047428553.1	c.24C>G	p.His8Gln	missense_variant	2/17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.24C>G	p.His8Gln	missense_variant	2/17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.24C>G	p.His8Gln	missense_variant	1/16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.24C>G	p.His8Gln	missense_variant	2/18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SETD1B-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2022

The SETD1B c.24C>G variant is predicted to result in the amino acid substitution p.His8Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Benign	0.88
DEOGEN2	Benign	0.0076	T;.;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.42	.;T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.1	L;L;.;L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.3	.;N;N;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0070	.;D;D;.
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.60	P;.;.;P
Vest4		0.24
MutPred		0.080		Loss of glycosylation at P7 (P = 0.0715);Loss of glycosylation at P7 (P = 0.0715);Loss of glycosylation at P7 (P = 0.0715);Loss of glycosylation at P7 (P = 0.0715);
MVP		0.80
MPC		2.1
ClinPred		0.41	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.55

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-122242667;