Genetic Variant NSD2:c.*3199G>T (chr4-1982108-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

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 FAILED quality control check.

BS2

High AC in GnomAd4 at 286 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD2	NM_001042424.3 link	c.*3199G>T		3_prime_UTR_variant	Exon 22 of 22	ENST00000508803.6	NP_001035889.1	O96028-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD2	ENST00000508803.6 link	c.*3199G>T		3_prime_UTR_variant	Exon 22 of 22	1	NM_001042424.3	ENSP00000423972.1		O96028-1

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152232

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00290

AC XY:

359

AN XY:

123874

show subpopulations

Gnomad4 AFR exome

AF:

0.000838

AC:

AN:

7162

Gnomad4 AMR exome

AF:

0.000810

AC:

AN:

7406

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

9210

Gnomad4 EAS exome

AF:

0.0000438

AC:

AN:

22840

Gnomad4 SAS exome

AF:

0.00229

AC:

AN:

2182

Gnomad4 FIN exome

AF:

0.00218

AC:

AN:

20648

Gnomad4 NFE exome

AF:

0.00357

AC:

562

AN:

157382

Gnomad4 Remaining exome

AF:

0.00202

AC:

AN:

16304

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00188

AC:

286

AN:

152350

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000577

AC:

0.000577228

AN:

0.000577228

Gnomad4 AMR

AF:

0.000588

AC:

0.000587928

AN:

0.000587928

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000193

AC:

0.000192827

AN:

0.000192827

Gnomad4 SAS

AF:

0.00248

AC:

0.00248344

AN:

0.00248344

Gnomad4 FIN

AF:

0.00160

AC:

0.00160015

AN:

0.00160015

Gnomad4 NFE

AF:

0.00307

AC:

0.00307208

AN:

0.00307208

Gnomad4 OTH

AF:

0.00237

AC:

0.00236518

AN:

0.00236518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.00186

Asia WGS

AF:

0.00173

AC:

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

DANN

Benign

0.76

Mutation Taster

=99/1

polymorphism

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over