12-121804799-C-A

Position:

• chr12-121804799-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001353345.2(SETD1B):​c.62C>A​(p.Ser21*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD1B NM_001353345.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.34

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-121804799-C-A is Pathogenic according to our data. Variant chr12-121804799-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2438172.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.62C>A	p.Ser21*	stop_gained	Exon 2 of 17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.62C>A	p.Ser21*	stop_gained	Exon 2 of 17		XP_024304666.1
SETD1B	XM_047428552.1	c.62C>A	p.Ser21*	stop_gained	Exon 2 of 17		XP_047284508.1
SETD1B	XM_047428553.1	c.62C>A	p.Ser21*	stop_gained	Exon 2 of 17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.62C>A	p.Ser21*	stop_gained	Exon 2 of 17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.62C>A	p.Ser21*	stop_gained	Exon 1 of 16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.62C>A	p.Ser21*	stop_gained	Exon 2 of 18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with seizures and language delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.26
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: chr12-122242705;