5-177294197-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022455.5(NSD1):c.6829T>C(p.Leu2277Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 1,614,048 control chromosomes in the GnomAD database, including 602,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.86 ( 57248 hom., cov: 32)

Exomes 𝑓: 0.86 ( 544869 hom. )

Consequence

NSD1
NM_022455.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0440

Publications

40 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 5-177294197-T-C is Benign according to our data. Variant chr5-177294197-T-C is described in ClinVar as Benign. ClinVar VariationId is 96073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.044 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.915 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.6829T>C	p.Leu2277Leu	synonymous_variant	Exon 23 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.6829T>C	p.Leu2277Leu	synonymous_variant	Exon 23 of 23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes

AF:

0.863

AC:

131293

AN:

152102

Hom.:

57193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.922

Gnomad AMI

AF:

0.943

Gnomad AMR

AF:

0.827

Gnomad ASJ

AF:

0.886

Gnomad EAS

AF:

0.489

Gnomad SAS

AF:

0.753

Gnomad FIN

AF:

0.812

Gnomad MID

AF:

0.911

Gnomad NFE

AF:

0.877

Gnomad OTH

AF:

0.874

GnomAD2 exomes

AF:

0.819

AC:

205884

AN:

251248

AF XY:

0.822

show subpopulations

Gnomad AFR exome

AF:

0.924

Gnomad AMR exome

AF:

0.763

Gnomad ASJ exome

AF:

0.886

Gnomad EAS exome

AF:

0.481

Gnomad FIN exome

AF:

0.816

Gnomad NFE exome

AF:

0.880

Gnomad OTH exome

AF:

0.847

GnomAD4 exome

AF:

0.860

AC:

1257229

AN:

1461828

Hom.:

544869

Cov.:

AF XY:

0.858

AC XY:

623843

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.930

AC:

31123

AN:

33480

American (AMR)

AF:

0.774

AC:

34635

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.885

AC:

23135

AN:

26136

East Asian (EAS)

AF:

0.490

AC:

19450

AN:

39700

South Asian (SAS)

AF:

0.782

AC:

67412

AN:

86254

European-Finnish (FIN)

AF:

0.814

AC:

43469

AN:

53390

Middle Eastern (MID)

AF:

0.884

AC:

5097

AN:

5768

European-Non Finnish (NFE)

AF:

0.883

AC:

981600

AN:

1111980

Other (OTH)

AF:

0.850

AC:

51308

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

11218

22436

33654

44872

56090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21280

42560

63840

85120

106400

<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:

0.863

AC:

131410

AN:

152220

Hom.:

57248

Cov.:

AF XY:

0.855

AC XY:

63635

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.923

AC:

38321

AN:

41536

American (AMR)

AF:

0.827

AC:

12647

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.886

AC:

3077

AN:

3472

East Asian (EAS)

AF:

0.490

AC:

2527

AN:

5162

South Asian (SAS)

AF:

0.752

AC:

3629

AN:

4826

European-Finnish (FIN)

AF:

0.812

AC:

8602

AN:

10592

Middle Eastern (MID)

AF:

0.912

AC:

268

AN:

294

European-Non Finnish (NFE)

AF:

0.877

AC:

59633

AN:

68020

Other (OTH)

AF:

0.873

AC:

1846

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

884

1769

2653

3538

4422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<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:

0.878

Hom.:

34686

Bravo

AF:

0.868

Asia WGS

AF:

0.666

AC:

2322

AN:

3478

EpiCase

AF:

0.884

EpiControl

AF:

0.889

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 03, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely 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

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 11, 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. -

not provided

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sotos syndrome

Benign:1

Sep 05, 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

-0.91

CADD

Benign

3.8

(source)

DANN

Benign

0.73

PhyloP100

-0.044

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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