16-30980736-CAG-C

Variant names:

• chr16-30980736-CAG-C
• rs755127868
• NM_014712.3:c.4582-2_4582-1delAG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PVS1_Moderate PP5_Moderate BS2

The NM_014712.3(SETD1A):​c.4582-2_4582-1delAG variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000822 in 1,459,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SETD1A NM_014712.3 splice_acceptor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.06
• Publications: 1 publications found

Genes affected

SETD1A (HGNC:29010): (SET domain containing 1A, histone lysine methyltransferase) The protein encoded by this gene is a component of a histone methyltransferase (HMT) complex that produces mono-, di-, and trimethylated histone H3 at Lys4. Trimethylation of histone H3 at lysine 4 (H3K4me3) is a chromatin modification known to generally mark the transcription start sites of active genes. The protein contains SET domains, a RNA recognition motif domain and is a member of the class V-like SAM-binding methyltransferase superfamily. [provided by RefSeq, Dec 2016]

SETD1A Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with speech impairment and dysmorphic facies

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• epilepsy, early-onset, with or without developmental delay

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.021662764 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 16-30980736-CAG-C is Pathogenic according to our data. Variant chr16-30980736-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 417721.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 12 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014712.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1A	NM_014712.3	MANE Select	c.4582-2_4582-1delAG		splice_acceptor intron	N/A	NP_055527.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1A	ENST00000262519.14	TSL:1 MANE Select	c.4582-2_4582-1delAG		splice_acceptor intron	N/A	ENSP00000262519.8
	SETD1A	ENST00000684162.1		c.4582-2_4582-1delAG		splice_acceptor intron	N/A	ENSP00000507683.1
	SETD1A	ENST00000710314.1		c.4582-2_4582-1delAG		splice_acceptor intron	N/A	ENSP00000518195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247796 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459960 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 726314

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26032

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.0000382 AC: 2 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111568

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 14, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neurodevelopmental disorder with speech impairment and dysmorphic facies Pathogenic:2

Mar 21, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant was shown to cause retention of intron 15 and a premature termination codon in exon 16, therefore resulting in nonsense-mediated decay (NMD) (PMID: 32346159, 26974950); Variant is present in gnomAD <0.001 for a dominant condition (v4: 12 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar, and reported in the literature in individuals with SETD1A-related features (DECIPHER; PMID: 32346159, 26974950); Another canonical splice site variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.4582-2A>G variant has been reported in the literature in one individual with bipolar disorder (PMID: 38646907). Additional information: This variant is heterozygous; This gene is associated with autosomal dominant disease; Alternative nucleotide change(s) at the same canonical splice site are present in gnomAD (Highest allele count: v4: 15 heterozygote(s), 0 homozygote(s)); Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with speech impairment and dysmorphic facies (MIM#619056), whereas the mechanism is unknown for early onset epilepsy with or without developmental delay (MIM#619056); Variants in this gene are known to have variable expressivity (OMIM, PMID: 37918557); Inheritance information for this variant is not currently available in this individual.

Nov 07, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 1.00 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. The variant has been previously reported as de novo in a similarly affected individual (PMID: 24853937).The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000417721 /PMID: 24853937). Therefore, this variant is classified as Pathogenic (PVS1_VS, PS2_S, PM2_M, PP5_M) according to the recommendation of ACMG/AMP guideline.

Epilepsy, early-onset, with or without developmental delay Pathogenic:1

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 3

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

Other links and lift over

dbSNP: rs755127868; hg19: chr16-30992057;