rs34165241

Variant names:

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.6782T>C(p.Met2261Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0515 in 1,614,106 control chromosomes in the GnomAD database, including 2,505 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M2261V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.049 ( 199 hom., cov: 31)

Exomes 𝑓: 0.052 ( 2306 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.209

Publications

25 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=0.0013430119).

BP6

Variant 5-177294150-T-C is Benign according to our data. Variant chr5-177294150-T-C is described in ClinVar as Benign. ClinVar VariationId is 96071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.6782T>C	p.Met2261Thr	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.6782T>C	p.Met2261Thr	missense_variant	Exon 23 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.0486

AC:

7400

AN:

152140

Hom.:

198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0175

Gnomad SAS

AF:

0.0822

Gnomad FIN

AF:

0.0418

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0515

Gnomad OTH

AF:

0.0426

GnomAD2 exomes

AF:

0.0466

AC:

11716

AN:

251250

AF XY:

0.0484

show subpopulations

Gnomad AFR exome

AF:

0.0592

Gnomad AMR exome

AF:

0.0197

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.0190

Gnomad FIN exome

AF:

0.0434

Gnomad NFE exome

AF:

0.0500

Gnomad OTH exome

AF:

0.0464

GnomAD4 exome

AF:

0.0518

AC:

75775

AN:

1461848

Hom.:

2306

Cov.:

AF XY:

0.0528

AC XY:

38373

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0570

AC:

1910

AN:

33480

American (AMR)

AF:

0.0217

AC:

971

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0194

AC:

506

AN:

26134

East Asian (EAS)

AF:

0.0170

AC:

674

AN:

39700

South Asian (SAS)

AF:

0.0837

AC:

7218

AN:

86258

European-Finnish (FIN)

AF:

0.0446

AC:

2381

AN:

53406

Middle Eastern (MID)

AF:

0.0671

AC:

387

AN:

5768

European-Non Finnish (NFE)

AF:

0.0527

AC:

58637

AN:

1111984

Other (OTH)

AF:

0.0512

AC:

3091

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

4752

9504

14255

19007

23759

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:

7409

AN:

152258

Hom.:

199

Cov.:

AF XY:

0.0477

AC XY:

3553

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0549

AC:

2279

AN:

41530

American (AMR)

AF:

0.0325

AC:

497

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3468

East Asian (EAS)

AF:

0.0175

AC:

AN:

5190

South Asian (SAS)

AF:

0.0821

AC:

396

AN:

4826

European-Finnish (FIN)

AF:

0.0418

AC:

443

AN:

10604

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0515

AC:

3502

AN:

68018

Other (OTH)

AF:

0.0450

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

365

730

1094

1459

1824

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:

0.0498

Hom.:

762

Bravo

AF:

0.0468

TwinsUK

AF:

0.0580

AC:

215

ALSPAC

AF:

0.0501

AC:

193

ESP6500AA

AF:

0.0588

AC:

259

ESP6500EA

AF:

0.0488

AC:

420

ExAC

AF:

0.0491

AC:

5966

Asia WGS

AF:

0.0880

AC:

305

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

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

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

- -

Jun 10, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

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

0.055

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.032

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.056

.;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.19

T;T;.

MetaRNN

Benign

0.0013

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

-0.55

.;N;.

PhyloP100

-0.21

PrimateAI

Benign

0.30

PROVEAN

Benign

0.58

N;N;N

REVEL

Benign

0.20

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.89

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.017

MPC

0.16

ClinPred

0.00014

GERP RS

-2.0

Varity_R

0.024

gMVP

0.13

Mutation Taster

=100/0

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