chr4-1938448-TAGAG-T

Variant names:

• chr4-1938448-TAGAG-T
• rs1553873247
• NM_001042424.3:c.1676_1679delGAGA

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001042424.3(NSD2):​c.1676_1679delGAGA​(p.Arg559fs) variant causes a frameshift, splice region 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: NSD2 NM_001042424.3 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.97
• Publications: 2 publications found

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]

NSD2 Gene-Disease associations (from GenCC):

• Rauch-Steindl syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Wolf-Hirschhorn syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 547999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042424.3. 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
	NSD2	NM_001042424.3	MANE Select	c.1676_1679delGAGA	p.Arg559fs	frameshift splice_region	Exon 8 of 22	NP_001035889.1
	NSD2	NM_001440893.1		c.1775_1778delGAGA	p.Arg592fs	frameshift splice_region	Exon 8 of 22	NP_001427822.1
	NSD2	NM_001440892.1		c.1676_1679delGAGA	p.Arg559fs	frameshift splice_region	Exon 9 of 23	NP_001427821.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD2	ENST00000508803.6	TSL:1 MANE Select	c.1676_1679delGAGA	p.Arg559fs	frameshift splice_region	Exon 8 of 22	ENSP00000423972.1
	NSD2	ENST00000382892.6	TSL:1	c.1676_1679delGAGA	p.Arg559fs	frameshift splice_region	Exon 9 of 23	ENSP00000372348.2
	NSD2	ENST00000382895.7	TSL:1	c.1676_1679delGAGA	p.Arg559fs	frameshift splice_region	Exon 10 of 24	ENSP00000372351.3

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

⚠️ 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: 20718

American (AMR) AF: 0.00 AC: 0 AN: 33382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20058

East Asian (EAS) AF: 0.00 AC: 0 AN: 32470

South Asian (SAS) AF: 0.00 AC: 0 AN: 66494

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 46950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2908

European-Non Finnish (NFE) AF: 0.00000158 AC: 1 AN: 632278

Other (OTH) AF: 0.00 AC: 0 AN: 39520

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 18

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Rauch-Steindl syndrome (4)
3	-	-	not provided (3)
1	-	-	4p partial monosomy syndrome (1)
1	-	-	Global developmental delay (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	NSD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553873247; hg19: chr4-1940175;