12-121805153-TC-T

Position:

• chr12-121805153-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001353345.2(SETD1B):​c.214delC​(p.Arg72fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD1B NM_001353345.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.72

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-121805153-TC-T is Pathogenic according to our data. Variant chr12-121805153-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 1992426.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.214delC	p.Arg72fs	frameshift_variant	3/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.214delC	p.Arg72fs	frameshift_variant	3/17		XP_024304666.1
SETD1B	XM_047428552.1	c.214delC	p.Arg72fs	frameshift_variant	3/17		XP_047284508.1
SETD1B	XM_047428553.1	c.214delC	p.Arg72fs	frameshift_variant	3/17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.214delC	p.Arg72fs	frameshift_variant	3/17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.214delC	p.Arg72fs	frameshift_variant	2/16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.214delC	p.Arg72fs	frameshift_variant	3/18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

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

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Dec 31, 2022

A heterozygous single base pair deletion in exon 3 of the SETD1B gene that results in a frameshift and premature truncation of the protein 34 amino acids downstream to codon 72 (p.Arg72GlyfsTer34) was detected. This variant has not been detected in the 1000 genomes, gnomAD and our internal databases. The in silico predictions of the variant is damaging by MutationTaster 2. The reference codon is conserved across species.. In summary, the variant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: chr12-122243059;