4-1982108-G-T

Variant names:

• chr4-1982108-G-T
• rs14647
• NM_001042424.3:c.*3199G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_001042424.3(NSD2):​c.*3199G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 396,772 control chromosomes in the GnomAD database, including 4 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 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (2 hom.)
• Consequence: NSD2 NM_001042424.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 3 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00188 (286/152350) while in subpopulation NFE AF = 0.00307 (209/68032). AF 95% confidence interval is 0.00273. There are 2 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 286 AD gene.

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.*3199G>T		3_prime_UTR	Exon 22 of 22	NP_001035889.1	O96028-1
	NSD2	NM_001440893.1		c.*3199G>T		3_prime_UTR	Exon 22 of 22	NP_001427822.1
	NSD2	NM_001440892.1		c.*3199G>T		3_prime_UTR	Exon 23 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.*3199G>T		3_prime_UTR	Exon 22 of 22	ENSP00000423972.1	O96028-1
	NSD2	ENST00000382892.6	TSL:1	c.*3199G>T		3_prime_UTR	Exon 23 of 23	ENSP00000372348.2	O96028-1
	NSD2	ENST00000382895.7	TSL:1	c.*3199G>T		3_prime_UTR	Exon 24 of 24	ENSP00000372351.3	O96028-1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152232 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00270 AC: 661 AN: 244422 Hom.: 2 Cov.: 0 AF XY: 0.00290 AC XY: 359 AN XY: 123874

African (AFR) AF: 0.000838 AC: 6 AN: 7162

American (AMR) AF: 0.000810 AC: 6 AN: 7406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9210

East Asian (EAS) AF: 0.0000438 AC: 1 AN: 22840

South Asian (SAS) AF: 0.00229 AC: 5 AN: 2182

European-Finnish (FIN) AF: 0.00218 AC: 45 AN: 20648

Middle Eastern (MID) AF: 0.00233 AC: 3 AN: 1288

European-Non Finnish (NFE) AF: 0.00357 AC: 562 AN: 157382

Other (OTH) AF: 0.00202 AC: 33 AN: 16304

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152350 Hom.: 2 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74510

African (AFR) AF: 0.000577 AC: 24 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4832

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00307 AC: 209 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.00186

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		1.0
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs14647; hg19: chr4-1983835;