Genetic Variant NSD3:p.Arg815His (chr8-38304754-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_023034.2(NSD3):c.2444G>A(p.Arg815His) variant causes a missense change. The variant allele was found at a frequency of 0.0000249 in 1,603,494 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R815C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

NSD3
NM_023034.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.17

Variant links:

Genes affected

NSD3 (HGNC:12767): (nuclear receptor binding SET domain protein 3) This gene is related to the Wolf-Hirschhorn syndrome candidate-1 gene and encodes a protein with PWWP (proline-tryptophan-tryptophan-proline) domains. This protein methylates histone H3 at lysine residues 4 and 27, which represses gene transcription. Two alternatively spliced variants have been described. [provided by RefSeq, May 2015]

NSD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD3	NM_023034.2 link	c.2444G>A	p.Arg815His	missense_variant	Exon 14 of 24	ENST00000317025.13	NP_075447.1	Q9BZ95-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NSD3	ENST00000317025.13 link	c.2444G>A	p.Arg815His	missense_variant	Exon 14 of 24	1	NM_023034.2	ENSP00000313983.7	Q9BZ95-1
NSD3	ENST00000527502.5 link	c.2444G>A	p.Arg815His	missense_variant	Exon 14 of 24	1		ENSP00000434730.1	Q9BZ95-5
NSD3	ENST00000433384.6 link	c.2444G>A	p.Arg815His	missense_variant	Exon 14 of 23	1		ENSP00000393284.2	Q9BZ95-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000549

AC:

AN:

236848

AF XY:

0.0000699

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.000190

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000486

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1451316

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

721830

show subpopulations

African (AFR)

AF:

0.000182

AC:

AN:

32942

American (AMR)

AF:

0.000212

AC:

AN:

42514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25552

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.0000475

AC:

AN:

84132

European-Finnish (FIN)

AF:

0.0000572

AC:

AN:

52488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00000812

AC:

AN:

1108466

Other (OTH)

AF:

0.0000500

AC:

AN:

59956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41434

American (AMR)

AF:

0.000196

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2444G>A (p.R815H) alteration is located in exon 14 (coding exon 13) of the WHSC1L1 gene. This alteration results from a G to A substitution at nucleotide position 2444, causing the arginine (R) at amino acid position 815 to be replaced by a histidine (H). 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

0.20

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.9

L;L;L

PhyloP100

6.2

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.68

MVP

0.77

MPC

1.5

ClinPred

0.64

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.67

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

Loading publications...

8-38304754-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over