12-121805218-T-C

Variant names:

• chr12-121805218-T-C
• NM_001353345.2:c.273+2T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001353345.2(SETD1B):​c.273+2T>C variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD1B NM_001353345.2 splice_donor, intron
• Scores: Splicing: ADA: 0.5357
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.82

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 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.016776817 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.273+2T>C		splice_donor_variant, intron_variant	Intron 3 of 16	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.273+2T>C		splice_donor_variant, intron_variant	Intron 3 of 16		XP_024304666.1
SETD1B	XM_047428552.1	c.273+2T>C		splice_donor_variant, intron_variant	Intron 3 of 16		XP_047284508.1
SETD1B	XM_047428553.1	c.273+2T>C		splice_donor_variant, intron_variant	Intron 3 of 16		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.273+2T>C		splice_donor_variant, intron_variant	Intron 3 of 16	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.273+2T>C		splice_donor_variant, intron_variant	Intron 2 of 15	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.273+2T>C		splice_donor_variant, intron_variant	Intron 3 of 17	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder with seizures and language delay Uncertain:2

Apr 04, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.273+2T>C variant in the SETD1B gene has not been previously reported in association with disease. This variant has been submitted to ClinVar (Variation ID: 2435853, ncbi.nlm.nih.gov/clinvar/), and was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The c.273+2T>C variant alters the canonical donor splice site in intron 3, which is predicted to result in abnormal gene splicing. These predictions have not been tested directly. Heterozygous loss of function leading to haploinsufficiency of the SETD1B gene is an established mechanism of disease; however, splice variants have not been widely reported in affected individuals. Using ACMG guidelines, this variant was classified as a variant of uncertain significance (ACMG evidence codes used: PVS1_moderate, PM2_supporting). -

Nov 01, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Benign	0.94
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.86	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.13		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: chr12-122243124;