Genetic Variant SETD1B:p.His8ProfsTer30 (chr12-121804751-A-AC) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_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. 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 1.79

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 4 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 id is 2236999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SETD1B	NM_001353345.2 link	c.22dupC	p.His8ProfsTer30	frameshift_variant	Exon 2 of 17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2 link	c.22dupC	p.His8ProfsTer30	frameshift_variant	Exon 2 of 17		XP_024304666.1
SETD1B	XM_047428552.1 link	c.22dupC	p.His8ProfsTer30	frameshift_variant	Exon 2 of 17		XP_047284508.1
SETD1B	XM_047428553.1 link	c.22dupC	p.His8ProfsTer30	frameshift_variant	Exon 2 of 17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SETD1B	ENST00000604567.6 link	c.22dupC	p.His8ProfsTer30	frameshift_variant	Exon 2 of 17	5	NM_001353345.2	ENSP00000474253.1	Q9UPS6-1
SETD1B	ENST00000619791.1 link	c.22dupC	p.His8ProfsTer30	frameshift_variant	Exon 1 of 16	1		ENSP00000481531.1	Q9UPS6-1
SETD1B	ENST00000542440.5 link	c.22dupC	p.His8ProfsTer30	frameshift_variant	Exon 2 of 18	5		ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes

AF:

0.00000713

AC:

AN:

140262

Hom.:

Cov.:

show subpopulations

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

GnomAD4 exome

AF:

0.0000606

AC:

AN:

1386942

Hom.:

Cov.:

AF XY:

0.0000614

AC XY:

AN XY:

684176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000641

Gnomad4 AMR exome

AF:

0.0000573

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00139

Gnomad4 NFE exome

AF:

0.00000933

Gnomad4 OTH exome

AF:

0.0000523

GnomAD4 genome

AF:

0.00000713

AC:

AN:

140262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

67910

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000708

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

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual developmental disorder with seizures and language delay

Pathogenic:5

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder with seizures and language delay (MIM#619000). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in heterozygous de novo individuals with SETD1B-related symptoms (PMID: 34345025). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 20, 2024

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified by standard clinical testing. de novo in a male patient with speech-related developmental disorder, myoclonic atonic therapy-refractory epilepsy and behavioral problems. Selected ACMG criteria: Pathogenic (I):PP5;PS2;PVS1 -

Sep 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SETD1B c.22dupC (p.His8ProfsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.5e-05 in 136830 control chromosomes, however, this finding should be interpretted with caution as metrics indicate poor quality at this region in the gnomAD database, suggesting this data is unreliable. c.22dupC has been reported in the literature in the heterozygous state in two unrelated individuals affected with Intellectual Developmental Disorder With Seizures And Language Delay, where in both cases it was found to be de novo (Weerts_2021). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34345025). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 29, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS2,PS4_MOD -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Inborn genetic diseases

Pathogenic:1

Jan 08, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22dupC (p.H8Pfs*30) alteration, located in exon 1 (coding exon 1) of the SETD1B gene, consists of a duplication of C at position 22, causing a translational frameshift with a predicted alternate stop codon after 30 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in two individuals with features consistent with SETD1B-related neurodevelopmental disorder (Weerts, 2021). Based on the available evidence, this alteration is classified as pathogenic. -

Neurodevelopmental disorder

Pathogenic:1

May 17, 2023

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over