12-121804751-ACCC-ACC

Variant names:

• chr12-121804751-AC-A
• rs777278685
• NM_001353345.2:c.22delC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_001353345.2(SETD1B):​c.22delC​(p.His8ThrfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,386,526 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SETD1B NM_001353345.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79

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: 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 55 pathogenic variants in the truncated region.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.22delC	p.His8ThrfsTer27	frameshift_variant	Exon 2 of 17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.22delC	p.His8ThrfsTer27	frameshift_variant	Exon 2 of 17		XP_024304666.1
SETD1B	XM_047428552.1	c.22delC	p.His8ThrfsTer27	frameshift_variant	Exon 2 of 17		XP_047284508.1
SETD1B	XM_047428553.1	c.22delC	p.His8ThrfsTer27	frameshift_variant	Exon 2 of 17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.22delC	p.His8ThrfsTer27	frameshift_variant	Exon 2 of 17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.22delC	p.His8ThrfsTer27	frameshift_variant	Exon 1 of 16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.22delC	p.His8ThrfsTer27	frameshift_variant	Exon 2 of 18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 140262 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 23 AN: 1386526 Hom.: 0 Cov.: 33 AF XY: 0.0000219 AC XY: 15 AN XY: 683982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000143

Gnomad4 ASJ exome AF: 0.0000403

Gnomad4 EAS exome AF: 0.0000283

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.0000140

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 140262 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 67910

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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

LitVar

Other links and lift over

dbSNP: rs777278685; hg19: chr12-122242657;