rs28932177

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_StrongBS1BS2

The NM_022455.5(NSD1):c.2071G>A(p.Ala691Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,614,110 control chromosomes in the GnomAD database, including 608 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A691A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 32 hom., cov: 32)

Exomes 𝑓: 0.025 ( 576 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.462

Publications

23 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=0.0032784045).

BP6

Variant 5-177210470-G-A is Benign according to our data. Variant chr5-177210470-G-A is described in ClinVar as Benign. ClinVar VariationId is 159279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0182 (2778/152266) while in subpopulation NFE AF = 0.0282 (1919/68008). AF 95% confidence interval is 0.0272. There are 32 homozygotes in GnomAd4. There are 1334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2778 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.2071G>A	p.Ala691Thr	missense_variant	Exon 5 of 23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7 link	c.2071G>A	p.Ala691Thr	missense_variant	Exon 5 of 23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2781

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00444

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00831

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0302

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0282

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0205

AC:

5162

AN:

251228

AF XY:

0.0215

show subpopulations

Gnomad AFR exome

AF:

0.00501

Gnomad AMR exome

AF:

0.00766

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0253

AC:

36996

AN:

1461844

Hom.:

576

Cov.:

AF XY:

0.0255

AC XY:

18578

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00349

AC:

117

AN:

33480

American (AMR)

AF:

0.00821

AC:

367

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0142

AC:

371

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0299

AC:

2576

AN:

86258

European-Finnish (FIN)

AF:

0.0310

AC:

1657

AN:

53410

Middle Eastern (MID)

AF:

0.0333

AC:

192

AN:

5768

European-Non Finnish (NFE)

AF:

0.0274

AC:

30434

AN:

1111974

Other (OTH)

AF:

0.0212

AC:

1282

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2150

4300

6449

8599

10749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1102

2204

3306

4408

5510

<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:

0.0182

AC:

2778

AN:

152266

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1334

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00443

AC:

184

AN:

41546

American (AMR)

AF:

0.00830

AC:

127

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5180

South Asian (SAS)

AF:

0.0267

AC:

129

AN:

4828

European-Finnish (FIN)

AF:

0.0302

AC:

321

AN:

10622

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0282

AC:

1919

AN:

68008

Other (OTH)

AF:

0.0128

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

142

284

427

569

711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0239

Hom.:

183

Bravo

AF:

0.0151

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0244

AC:

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.0241

AC:

207

ExAC

AF:

0.0209

AC:

2534

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0276

EpiControl

AF:

0.0219

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

PreventionGenetics, part of Exact Sciences

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

- -

Mar 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28146470) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 29, 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

0.066

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.052

.;T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.80

T;T;.

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.2

.;L;.

PhyloP100

0.46

PrimateAI

Benign

0.27

PROVEAN

Benign

0.22

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.0060

B;B;B

Vest4

0.056

MPC

0.054

ClinPred

0.0027

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.028

gMVP

0.14

Mutation Taster

=96/4

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