4-1900665-G-A

Position:

chr4-1900665-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_001042424.3(NSD2):c.11G>A(p.Ser4Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000727 in 1,580,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

NSD2
NM_001042424.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.1190941).

BP6

Variant 4-1900665-G-A is Benign according to our data. Variant chr4-1900665-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 348417.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000735 (105/1428816) while in subpopulation MID AF= 0.00196 (11/5618). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4_exome. There are 61 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD2	NM_001042424.3 linkuse as main transcript	c.11G>A	p.Ser4Asn	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.11G>A	p.Ser4Asn	missense_variant	2/22	1	NM_001042424.3	ENSP00000423972	P1	O96028-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000121

AC:

AN:

231082

Hom.:

AF XY:

0.0000882

AC XY:

AN XY:

124726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000335

Gnomad ASJ exome

AF:

0.000238

Gnomad EAS exome

AF:

0.0000562

Gnomad SAS exome

AF:

0.000190

Gnomad FIN exome

AF:

0.0000481

Gnomad NFE exome

AF:

0.0000752

Gnomad OTH exome

AF:

0.000179

GnomAD4 exome

AF:

0.0000735

AC:

105

AN:

1428816

Hom.:

Cov.:

AF XY:

0.0000863

AC XY:

AN XY:

707048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000254

Gnomad4 ASJ exome

AF:

0.000204

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.000316

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000411

Gnomad4 OTH exome

AF:

0.000102

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000122

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

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

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.4

L;.;L;.;L;L;L;L;L;.;L;L

MutationTaster

Benign

0.62

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

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.80

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

REVEL

Benign

0.17

Sift

Pathogenic

0.0

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

Sift4G

Benign

0.093

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

Polyphen

0.090

B;.;P;.;B;B;P;B;P;.;P;P

Vest4

0.16

MutPred

0.21

Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);Gain of glycosylation at S4 (P = 0.0419);

MVP

0.48

MPC

0.28

ClinPred

0.14

GERP RS

4.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.39

gMVP

0.19

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over