rs1553873247

chr4-1938448-TAGAG-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Moderate PM2 PP3_Moderate PP5_Very_Strong

The NM_001042424.3(NSD2):c.1676_1679del(p.Arg559ThrfsTer38) variant causes a splice acceptor, coding sequence change. The variant allele was found at a frequency of 0.00000224 in 894,778 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: 18)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: NSD2 NM_001042424.3 splice_acceptor, coding_sequence
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 5.97

Genes affected

NSD2 (HGNC:12766): (nuclear receptor binding SET domain protein 2) This gene encodes a protein that contains four domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain, and a PHD-type zinc finger. It is expressed ubiquitously in early development. Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4. This gene maps to the 165 kb WHS critical region and has also been involved in the chromosomal translocation t(4;14)(p16.3;q32.3) in multiple myelomas. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. Some transcript variants are nonsense-mediated mRNA (NMD) decay candidates, hence not represented as reference sequences. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.01976574 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of 0 (no position change), new splice context is: tttttttttttaaataatAGaca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-1938448-TAGAG-T is Pathogenic according to our data. Variant chr4-1938448-TAGAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 547999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1938448-TAGAG-T is described in Lovd as [Pathogenic]. Variant chr4-1938448-TAGAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD2	NM_001042424.3	c.1676_1679del	p.Arg559ThrfsTer38	splice_acceptor_variant, coding_sequence_variant	8/22	ENST00000508803.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD2	ENST00000508803.6	c.1676_1679del	p.Arg559ThrfsTer38	splice_acceptor_variant, coding_sequence_variant	8/22	1	NM_001042424.3	P1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome AF: 0.00000224 AC: 2 AN: 894778 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 463916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000213

Gnomad4 NFE exome AF: 0.00000158

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 18

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rauch-Steindl syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 26, 2022	The de novo c.1676_1679del variant identified in the NSD2 gene has previously been reported as de novo variant in individuals with NSD2-related disorder with features of developmental delay, cardiac defects, and multiple congenital malformations [PMID: 30345613, 26785492, 33144682] and it has been deposited in ClinVar [ClinVar ID: 547999] as Pathogenic. The c.1676_1679del variant is observed in 1 allele (~0.00062% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.1676_1679del variant in NSD2 is located in exon 8 of this 22-exon gene, predicted to incorporate a premature termination codon approximately 38 amino acids downstream (p.(Arg559ThrfsTer38)), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.1676_1679del variant have been reported in the literature [PMID: 31382906, 33941880] and ClinVar [ClinVar ID: 1333177] in individuals with Rauch-Steindl syndrome. Based on available evidence this de novo c.1676_1679del (p.(Arg559ThrfsTer38)), variant identified in NSD2 is classified here as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 17, 2022	PVS2, PS2, PM2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 11, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Sep 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33144682, 30345613, 26785492, 32368696, 33084842) -

Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Oct 25, 2021

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported to be associated with [GeneName] related disorder (ClinVar ID: VCV000547999.8). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

4p partial monosomy syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: 7
DS_AL_spliceai		0.90		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: rs1553873247; hg19: chr4-1940175;