rs35848863

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022455.5(NSD1):c.6750G>A(p.Met2250Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0516 in 1,614,000 control chromosomes in the GnomAD database, including 2,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.049 ( 199 hom., cov: 30)

Exomes 𝑓: 0.052 ( 2308 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0770

Publications

24 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=0.0012430251).

BP6

Variant 5-177294118-G-A is Benign according to our data. Variant chr5-177294118-G-A is described in ClinVar as Benign. ClinVar VariationId is 96070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.6750G>A	p.Met2250Ile	missense_variant	Exon 23 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.6750G>A	p.Met2250Ile	missense_variant	Exon 23 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.0487

AC:

7401

AN:

152058

Hom.:

198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0326

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0177

Gnomad SAS

AF:

0.0818

Gnomad FIN

AF:

0.0418

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0515

Gnomad OTH

AF:

0.0436

GnomAD2 exomes

AF:

0.0467

AC:

11724

AN:

251202

AF XY:

0.0485

show subpopulations

Gnomad AFR exome

AF:

0.0592

Gnomad AMR exome

AF:

0.0198

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.0191

Gnomad FIN exome

AF:

0.0434

Gnomad NFE exome

AF:

0.0501

Gnomad OTH exome

AF:

0.0466

GnomAD4 exome

AF:

0.0519

AC:

75817

AN:

1461824

Hom.:

2308

Cov.:

AF XY:

0.0528

AC XY:

38398

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0570

AC:

1910

AN:

33480

American (AMR)

AF:

0.0218

AC:

974

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

507

AN:

26136

East Asian (EAS)

AF:

0.0173

AC:

688

AN:

39700

South Asian (SAS)

AF:

0.0837

AC:

7217

AN:

86258

European-Finnish (FIN)

AF:

0.0446

AC:

2378

AN:

53378

Middle Eastern (MID)

AF:

0.0671

AC:

387

AN:

5768

European-Non Finnish (NFE)

AF:

0.0527

AC:

58639

AN:

1111986

Other (OTH)

AF:

0.0516

AC:

3117

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

4986

9972

14958

19944

24930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2208

4416

6624

8832

11040

<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:

0.0487

AC:

7410

AN:

152176

Hom.:

199

Cov.:

AF XY:

0.0478

AC XY:

3556

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0549

AC:

2278

AN:

41500

American (AMR)

AF:

0.0326

AC:

498

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.0178

AC:

AN:

5176

South Asian (SAS)

AF:

0.0816

AC:

393

AN:

4814

European-Finnish (FIN)

AF:

0.0418

AC:

443

AN:

10598

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0515

AC:

3503

AN:

68004

Other (OTH)

AF:

0.0460

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

358

716

1074

1432

1790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0495

Hom.:

746

Bravo

AF:

0.0469

TwinsUK

AF:

0.0580

AC:

215

ALSPAC

AF:

0.0498

AC:

192

ESP6500AA

AF:

0.0590

AC:

260

ESP6500EA

AF:

0.0488

AC:

420

ExAC

AF:

0.0492

AC:

5970

Asia WGS

AF:

0.0930

AC:

324

AN:

3478

EpiCase

AF:

0.0491

EpiControl

AF:

0.0449

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 10, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 13, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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. -

Sotos syndrome

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.067

.;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.71

T;T;.

MetaRNN

Benign

0.0012

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;N;.

PhyloP100

0.077

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.73

N;N;N

REVEL

Benign

0.066

Sift

Benign

0.043

D;D;D

Sift4G

Benign

0.17

T;T;T

Polyphen

0.095

B;B;B

Vest4

0.11

MutPred

0.057

.;Loss of catalytic residue at M2250 (P = 0.0214);.;

MPC

0.16

ClinPred

0.0019

GERP RS

1.5

Varity_R

0.070

gMVP

0.12

Mutation Taster

=97/3

polymorphism (auto)

(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