NM_022455.5:c.2339C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_022455.5(NSD1):c.2339C>T(p.Ser780Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000629 in 1,614,142 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S780S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 12 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.173

Publications

7 publications found

Variant links:

Genes affected

NSD1 (HGNC:14234): (nuclear receptor binding SET domain protein 1) This gene encodes a protein containing a SET domain, 2 LXXLL motifs, 3 nuclear translocation signals (NLSs), 4 plant homeodomain (PHD) finger regions, and a proline-rich region. The encoded protein enhances androgen receptor (AR) transactivation, and this enhancement can be increased further in the presence of other androgen receptor associated coregulators. This protein may act as a nucleus-localized, basic transcriptional factor and also as a bifunctional transcriptional regulator. Mutations of this gene have been associated with Sotos syndrome and Weaver syndrome. One version of childhood acute myeloid leukemia is the result of a cryptic translocation with the breakpoints occurring within nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1 on chromosome 5 and nucleoporin, 98-kd on chromosome 11. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Sep 2018]

NSD1 Gene-Disease associations (from GenCC):

Beckwith-Wiedemann syndrome due to NSD1 mutation
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Sotos syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
Sotos syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

NSD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071305633).

BP6

Variant 5-177210738-C-T is Benign according to our data. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210738-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 241432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000374 (57/152286) while in subpopulation SAS AF = 0.00788 (38/4820). AF 95% confidence interval is 0.0059. There are 2 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.2339C>T	p.Ser780Leu	missense_variant	Exon 5 of 23	ENST00000439151.7	NP_071900.2	Q96L73-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7 link	c.2339C>T	p.Ser780Leu	missense_variant	Exon 5 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00767

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00122

AC:

307

AN:

251328

AF XY:

0.00168

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000656

AC:

959

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000910

AC XY:

662

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39694

South Asian (SAS)

AF:

0.00784

AC:

676

AN:

86248

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00451

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000135

AC:

150

AN:

1112008

Other (OTH)

AF:

0.00126

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

140

211

281

351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000374

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41556

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00788

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000252

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00146

AC:

177

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NSD1: BS2 -

Sotos syndrome

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 15, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 20, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

NSD1-related disorder

Benign:1

Jul 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.067

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.84

T;T;.

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0071

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.67

.;N;.

PhyloP100

0.17

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.93

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.37

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.12

MVP

0.29

MPC

0.050

ClinPred

0.00033

GERP RS

2.0

Varity_R

0.023

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over