4-1900734-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001042424.3(NSD2):c.80T>G(p.Ile27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD2 NM_001042424.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NSD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.17433164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD2	NM_001042424.3	c.80T>G	p.Ile27Ser	missense_variant	2/22	ENST00000508803.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD2	ENST00000508803.6	c.80T>G	p.Ile27Ser	missense_variant	2/22	1	NM_001042424.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.;.;T;T;.;T;.;T;.;.
Eigen	Benign	0.098
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.8	L;.;L;.;L;L;L;L;L;.;L;L
MutationTaster	Benign	0.59	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.32	N;D;N;D;N;N;N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.14	T;D;T;D;T;T;T;T;T;T;T;T
Sift4G	Benign	0.14	T;D;D;D;T;T;D;T;D;D;D;D
Polyphen		0.027	B;.;D;.;B;B;D;B;D;.;D;D
Vest4		0.40
MutPred		0.30		Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);Gain of disorder (P = 0.0281);
MVP		0.65
MPC		0.45
ClinPred		0.31	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.096
gMVP		0.30

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: chr4-1902461;