4-1982108-G-T

Position:

• chr4-1982108-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD2	NM_001042424.3	c.*3199G>T		3_prime_UTR_variant	22/22	ENST00000508803.6	NP_001035889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD2	ENST00000508803.6	c.*3199G>T		3_prime_UTR_variant	22/22	1	NM_001042424.3	ENSP00000423972	P1

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

Gnomad4 AFR exome AF: 0.000838

Gnomad4 AMR exome AF: 0.000810

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000438

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.00218

Gnomad4 NFE exome AF: 0.00357

Gnomad4 OTH exome AF: 0.00202

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

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.00237

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs14647; hg19: chr4-1983835;