Genetic Variant NM_001042424.3:c.28C>T (chr4-1900682-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001042424.3(NSD2):c.28C>T(p.Leu10Phe) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L10V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NSD2
NM_001042424.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.81

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Rauch-Steindl syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Wolf-Hirschhorn syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

NSD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21336234).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042424.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NSD2	NM_001042424.3	MANE Select	c.28C>T	p.Leu10Phe	missense	Exon 2 of 22	NP_001035889.1	O96028-1
NSD2	NM_001440893.1		c.28C>T	p.Leu10Phe	missense	Exon 2 of 22	NP_001427822.1
NSD2	NM_001440892.1		c.28C>T	p.Leu10Phe	missense	Exon 3 of 23	NP_001427821.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NSD2	ENST00000508803.6	TSL:1 MANE Select	c.28C>T	p.Leu10Phe	missense	Exon 2 of 22	ENSP00000423972.1	O96028-1
NSD2	ENST00000382892.6	TSL:1	c.28C>T	p.Leu10Phe	missense	Exon 3 of 23	ENSP00000372348.2	O96028-1
NSD2	ENST00000382895.7	TSL:1	c.28C>T	p.Leu10Phe	missense	Exon 4 of 24	ENSP00000372351.3	O96028-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

M_CAP

Benign

0.082

MetaRNN

Benign

0.21

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.6

PhyloP100

2.8

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.25

REVEL

Benign

0.12

Sift

Benign

0.058

Sift4G

Benign

0.64

Polyphen

0.47

Vest4

0.17

MutPred

0.14

Gain of glycosylation at S11 (P = 0.0726)

MVP

0.57

MPC

0.68

ClinPred

0.60

GERP RS

4.8

PromoterAI

0.0042

Neutral

(source)

Varity_R

0.038

gMVP

0.11

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over