chr12-121804751-A-AC

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001353345.2(SETD1B):​c.22dupC​(p.His8ProfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000557 in 1,527,204 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: SETD1B NM_001353345.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 1.79
• Publications: 7 publications found

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]

SETD1B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with seizures and language delay

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 16 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 90 pathogenic variants in the truncated region.
• PP5: Variant 12-121804751-A-AC is Pathogenic according to our data. Variant chr12-121804751-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 2236999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1B	NM_001353345.2	MANE Select	c.22dupC	p.His8ProfsTer30	frameshift	Exon 2 of 17	NP_001340274.1	Q9UPS6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1B	ENST00000604567.6	TSL:5 MANE Select	c.22dupC	p.His8ProfsTer30	frameshift	Exon 2 of 17	ENSP00000474253.1	Q9UPS6-1
	SETD1B	ENST00000619791.1	TSL:1	c.22dupC	p.His8ProfsTer30	frameshift	Exon 1 of 16	ENSP00000481531.1	Q9UPS6-1
	SETD1B	ENST00000542440.5	TSL:5	c.22dupC	p.His8ProfsTer30	frameshift	Exon 2 of 18	ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes AF: 0.00000713 AC: 1 AN: 140262 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000708

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

GnomAD2 exomes AF: 0.0000950 AC: 13 AN: 136830 AF XY: 0.0000961

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.0000922

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000210

Gnomad FIN exome AF: 0.0000694

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000606 AC: 84 AN: 1386942 Hom.: 0 Cov.: 33 AF XY: 0.0000614 AC XY: 42 AN XY: 684176

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000641 AC: 2 AN: 31220

American (AMR) AF: 0.0000573 AC: 2 AN: 34934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24860

East Asian (EAS) AF: 0.00 AC: 0 AN: 35382

South Asian (SAS) AF: 0.00 AC: 0 AN: 78556

European-Finnish (FIN) AF: 0.00139 AC: 67 AN: 48164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5008

European-Non Finnish (NFE) AF: 0.00000933 AC: 10 AN: 1071416

Other (OTH) AF: 0.0000523 AC: 3 AN: 57402

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000713 AC: 1 AN: 140262 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 67910

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 37048

American (AMR) AF: 0.0000708 AC: 1 AN: 14126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3356

East Asian (EAS) AF: 0.00 AC: 0 AN: 4752

South Asian (SAS) AF: 0.00 AC: 0 AN: 4314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64392

Other (OTH) AF: 0.00 AC: 0 AN: 1908

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Intellectual developmental disorder with seizures and language delay (6)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=19/181	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777278685; hg19: chr12-122242657; COSMIC: COSV57348067; COSMIC: COSV57348067;