NM_022455.5:c.1749G>A

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.1749G>A(p.Glu583Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.138 in 1,612,332 control chromosomes in the GnomAD database, including 20,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1927 hom., cov: 31)

Exomes 𝑓: 0.14 ( 18162 hom. )

Consequence

NSD1
NM_022455.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.71

Publications

28 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 (BayesDel_noAF=-0.5).

BP6

Variant 5-177210148-G-A is Benign according to our data. Variant chr5-177210148-G-A is described in ClinVar as Benign. ClinVar VariationId is 96038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.1749G>A	p.Glu583Glu	synonymous_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.1749G>A	p.Glu583Glu	synonymous_variant	Exon 5 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.137

AC:

20788

AN:

152004

Hom.:

1930

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0818

Gnomad AMI

AF:

0.0571

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.113

Gnomad EAS

AF:

0.508

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.123

GnomAD2 exomes

AF:

0.179

AC:

44583

AN:

248928

AF XY:

0.177

show subpopulations

Gnomad AFR exome

AF:

0.0801

Gnomad AMR exome

AF:

0.234

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.516

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.119

Gnomad OTH exome

AF:

0.152

GnomAD4 exome

AF:

0.138

AC:

202175

AN:

1460210

Hom.:

18162

Cov.:

AF XY:

0.141

AC XY:

102108

AN XY:

726312

show subpopulations

African (AFR)

AF:

0.0744

AC:

2485

AN:

33412

American (AMR)

AF:

0.223

AC:

9871

AN:

44320

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2962

AN:

26044

East Asian (EAS)

AF:

0.504

AC:

19992

AN:

39674

South Asian (SAS)

AF:

0.217

AC:

18642

AN:

85888

European-Finnish (FIN)

AF:

0.186

AC:

9911

AN:

53390

Middle Eastern (MID)

AF:

0.117

AC:

672

AN:

5764

European-Non Finnish (NFE)

AF:

0.116

AC:

128640

AN:

1111408

Other (OTH)

AF:

0.149

AC:

9000

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

9820

19640

29461

39281

49101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4942

9884

14826

19768

24710

<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:

0.137

AC:

20788

AN:

152122

Hom.:

1927

Cov.:

AF XY:

0.145

AC XY:

10776

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0816

AC:

3387

AN:

41510

American (AMR)

AF:

0.170

AC:

2603

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

390

AN:

3466

East Asian (EAS)

AF:

0.507

AC:

2617

AN:

5158

South Asian (SAS)

AF:

0.249

AC:

1203

AN:

4826

European-Finnish (FIN)

AF:

0.188

AC:

1987

AN:

10584

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8262

AN:

67988

Other (OTH)

AF:

0.124

AC:

261

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

872

1744

2616

3488

4360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

242

484

726

968

1210

<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:

0.117

Hom.:

567

Bravo

AF:

0.132

Asia WGS

AF:

0.332

AC:

1151

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Jun 10, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 19, 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

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.8

(source)

DANN

Benign

0.51

PhyloP100

3.7

Mutation Taster

=98/2

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