NM_001042424.3:c.4074G>T

Variant names:

• chr4-1978885-G-T
• NM_001042424.3:c.4074G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001042424.3(NSD2):​c.4074G>T​(p.Trp1358Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,425,002 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NSD2 NM_001042424.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.13

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD2	NM_001042424.3	c.4074G>T	p.Trp1358Cys	missense_variant	Exon 22 of 22	ENST00000508803.6	NP_001035889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD2	ENST00000508803.6	c.4074G>T	p.Trp1358Cys	missense_variant	Exon 22 of 22	1	NM_001042424.3	ENSP00000423972.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425002 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;T;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	.;.;T;.;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L;L;L;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.52
MutPred		0.47		Gain of glycosylation at T1362 (P = 3e-04);Gain of glycosylation at T1362 (P = 3e-04);Gain of glycosylation at T1362 (P = 3e-04);Gain of glycosylation at T1362 (P = 3e-04);.;
MVP		0.27
MPC		0.0091
ClinPred		0.91	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-1980612;