12-121804751-ACCC-ACCCCCC

Variant names:

• chr12-121804751-A-ACCC
• rs777278685
• NM_001353345.2:c.20_22dupCCC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001353345.2(SETD1B):​c.20_22dupCCC​(p.Pro7dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,387,274 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SETD1B NM_001353345.2 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001353345.2

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.20_22dupCCC	p.Pro7dup	disruptive_inframe_insertion	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.20_22dupCCC	p.Pro7dup	disruptive_inframe_insertion	Exon 2 of 17	ENSP00000474253.1	Q9UPS6-1
	SETD1B	ENST00000619791.1	TSL:1	c.20_22dupCCC	p.Pro7dup	disruptive_inframe_insertion	Exon 1 of 16	ENSP00000481531.1	Q9UPS6-1
	SETD1B	ENST00000542440.5	TSL:5	c.20_22dupCCC	p.Pro7dup	disruptive_inframe_insertion	Exon 2 of 18	ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1387274 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 684348

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

African (AFR) AF: 0.00 AC: 0 AN: 31222

American (AMR) AF: 0.00 AC: 0 AN: 34942

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: 78562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48412

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

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1071482

Other (OTH) AF: 0.0000174 AC: 1 AN: 57404

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8

Splicing

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

Other links and lift over

dbSNP: rs777278685; hg19: chr12-122242657;