12-121805847-T-TACGTGGGA

Position:

• chr12-121805847-T-TACGTGGGA

Variant summary

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

The NM_001353345.2(SETD1B):​c.293_294insAACGTGGG​(p.Pro99fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. 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: 30)
• Consequence: SETD1B NM_001353345.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.26

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 12-121805847-T-TACGTGGGA is Pathogenic according to our data. Variant chr12-121805847-T-TACGTGGGA is described in ClinVar as [Pathogenic]. Clinvar id is 1679142.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.293_294insAACGTGGG	p.Pro99fs	frameshift_variant	4/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.293_294insAACGTGGG	p.Pro99fs	frameshift_variant	4/17		XP_024304666.1
SETD1B	XM_047428552.1	c.293_294insAACGTGGG	p.Pro99fs	frameshift_variant	4/17		XP_047284508.1
SETD1B	XM_047428553.1	c.293_294insAACGTGGG	p.Pro99fs	frameshift_variant	4/17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.293_294insAACGTGGG	p.Pro99fs	frameshift_variant	4/17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.293_294insAACGTGGG	p.Pro99fs	frameshift_variant	3/16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.293_294insAACGTGGG	p.Pro99fs	frameshift_variant	4/18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

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

Institute of Human Genetics, University of Leipzig Medical Center

Oct 18, 2022

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PM2_SUP, PS2_MOD -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr12-122243753;