rs10034373

Variant names:

• chr4-1980928-C-T
• rs10034373
• ENST00000312087.10:n.*4400C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000312087.10(NSD2):​n.*4400C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 233,184 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.040 (399 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (30 hom.)
• Consequence: NSD2 ENST00000312087.10 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000312087.10. 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
	NSD2	NM_001042424.3	MANE Select	c.*2019C>T		3_prime_UTR	Exon 22 of 22	NP_001035889.1
	NSD2	NM_001440893.1		c.*2019C>T		3_prime_UTR	Exon 22 of 22	NP_001427822.1
	NSD2	NM_001440892.1		c.*2019C>T		3_prime_UTR	Exon 23 of 23	NP_001427821.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD2	ENST00000312087.10	TSL:1	n.*4400C>T		non_coding_transcript_exon	Exon 25 of 25	ENSP00000308780.6
	NSD2	ENST00000353275.9	TSL:1	n.*4267C>T		non_coding_transcript_exon	Exon 25 of 25	ENSP00000329167.5
	NSD2	ENST00000508803.6	TSL:1 MANE Select	c.*2019C>T		3_prime_UTR	Exon 22 of 22	ENSP00000423972.1

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6136 AN: 152136 Hom.: 397 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.00862 AC: 698 AN: 80930 Hom.: 30 Cov.: 0 AF XY: 0.00785 AC XY: 292 AN XY: 37200

African (AFR) AF: 0.134 AC: 521 AN: 3896

American (AMR) AF: 0.0144 AC: 36 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 12 AN: 5124

East Asian (EAS) AF: 0.000351 AC: 4 AN: 11400

South Asian (SAS) AF: 0.00 AC: 0 AN: 702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 58

Middle Eastern (MID) AF: 0.00407 AC: 2 AN: 492

European-Non Finnish (NFE) AF: 0.000340 AC: 17 AN: 49994

Other (OTH) AF: 0.0157 AC: 106 AN: 6768

GnomAD4 genome AF: 0.0404 AC: 6152 AN: 152254 Hom.: 399 Cov.: 33 AF XY: 0.0389 AC XY: 2898 AN XY: 74444

African (AFR) AF: 0.141 AC: 5847 AN: 41498

American (AMR) AF: 0.0133 AC: 203 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68022

Other (OTH) AF: 0.0260 AC: 55 AN: 2116

Alfa AF: 0.0157 Hom.: 171

Bravo AF: 0.0466

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.90
DANN	Benign	0.81
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10034373; hg19: chr4-1982655;