Genetic Variant NM_001042424.3:c.11G>A (chr4-1900665-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_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

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

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 VariationId is 348417.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 61 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 10 AD gene.

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.11G>A	p.Ser4Asn	missense	Exon 2 of 22	NP_001035889.1	O96028-1
NSD2	NM_001440893.1		c.11G>A	p.Ser4Asn	missense	Exon 2 of 22	NP_001427822.1
NSD2	NM_001440892.1		c.11G>A	p.Ser4Asn	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.11G>A	p.Ser4Asn	missense	Exon 2 of 22	ENSP00000423972.1	O96028-1
NSD2	ENST00000382892.6	TSL:1	c.11G>A	p.Ser4Asn	missense	Exon 3 of 23	ENSP00000372348.2	O96028-1
NSD2	ENST00000382895.7	TSL:1	c.11G>A	p.Ser4Asn	missense	Exon 4 of 24	ENSP00000372351.3	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

GnomAD2 exomes

AF:

0.000121

AC:

AN:

231082

AF XY:

0.0000882

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 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

African (AFR)

AF:

0.00

AC:

AN:

32226

American (AMR)

AF:

0.000254

AC:

AN:

39360

Ashkenazi Jewish (ASJ)

AF:

0.000204

AC:

AN:

24566

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39264

South Asian (SAS)

AF:

0.000316

AC:

AN:

82162

European-Finnish (FIN)

AF:

0.0000189

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.00196

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.0000411

AC:

AN:

1093932

Other (OTH)

AF:

0.000102

AC:

AN:

58916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000208

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.12

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.4

PhyloP100

3.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.80

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Benign

0.093

Polyphen

0.090

Vest4

0.16

MutPred

0.21

Gain of glycosylation at S4 (P = 0.0419)

MVP

0.48

MPC

0.28

ClinPred

0.14

GERP RS

4.7

PromoterAI

0.012

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.39

gMVP

0.19

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over