Variant 4-1900722-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001042424.3(NSD2):c.68A>G(p.Gln23Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NSD2
NM_001042424.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NSD2. . Gene score misZ 3.8981 (greater than the threshold 3.09). Trascript score misZ 5.6522 (greater than threshold 3.09). GenCC has associacion of gene with Rauch-Steindl syndrome, syndromic intellectual disability, Wolf-Hirschhorn syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD2	NM_001042424.3 linkuse as main transcript	c.68A>G	p.Gln23Arg	missense_variant	2/22	ENST00000508803.6	NP_001035889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD2	ENST00000508803.6 linkuse as main transcript	c.68A>G	p.Gln23Arg	missense_variant	2/22	1	NM_001042424.3	ENSP00000423972	P1	O96028-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727138

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The c.68A>G (p.Q23R) alteration is located in exon 4 (coding exon 1) of the NSD2 (WHSC1) gene. This alteration results from a A to G substitution at nucleotide position 68, causing the glutamine (Q) at amino acid position 23 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;.;.;T;T;.;T;.;T;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.78

.;T;.;D;.;D;D;.;.;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.58

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

2.0

M;.;M;.;M;M;M;M;M;.;M;M

MutationTaster

Benign

0.97

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.2

N;D;N;D;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.29

T;D;D;D;T;T;D;T;D;D;D;D

Polyphen

0.99

D;.;D;.;D;D;D;D;D;.;D;D

Vest4

0.63

MutPred

0.23

Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);Gain of MoRF binding (P = 0.019);

MVP

0.97

MPC

0.94

ClinPred

0.85

GERP RS

5.6

Varity_R

0.36

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over