rs755127868

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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 Likely 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, single submitter P:5
• Conservation: PhyloP100: 6.06

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 [Likely_pathogenic]. Clinvar id is 417721.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-30980736-CAG-C is described in Lovd as [Likely_pathogenic]. Variant chr16-30980736-CAG-C is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1A	NM_014712.3	c.4582-2_4582-1delAG		splice_acceptor_variant, intron_variant	Intron 15 of 18	ENST00000262519.14	NP_055527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD1A	ENST00000262519.14	c.4582-2_4582-1delAG		splice_acceptor_variant, intron_variant	Intron 15 of 18	1	NM_014712.3	ENSP00000262519.8
SETD1A	ENST00000684162.1	c.4582-2_4582-1delAG		splice_acceptor_variant, intron_variant	Intron 15 of 18			ENSP00000507683.1
SETD1A	ENST00000710314.1	c.4582-2_4582-1delAG		splice_acceptor_variant, intron_variant	Intron 15 of 18			ENSP00000518195.1
SETD1A	ENST00000640410.1	n.606-2_606-1delAG		splice_acceptor_variant, intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000807 AC: 2 AN: 247796 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134434

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:3

-

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

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

- -

-

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

- -

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

- -

Neurodevelopmental disorder with speech impairment and dysmorphic facies Pathogenic:1

Jan 09, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.69 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.76 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000016337 /PMID: 7670477) and different missense changes at the same codon (p.Asn540Asp, p.Asn540His, p.Asn540Ser, p.Asn540Thr / ClinVar ID: VCV000016344, VCV000016349, VCV000374828, VCV001325830 / PMID: 10777366, 9452043) have been previously reported as pathogenic/likely pathogenic with strong evidence.The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 25614871). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs755127868; hg19: chr16-30992057;