chr5-177212104-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.3705T>C(p.Asn1235Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0607 in 1,613,878 control chromosomes in the GnomAD database, including 4,592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1321 hom., cov: 31)

Exomes 𝑓: 0.056 ( 3271 hom. )

Consequence

NSD1
NM_022455.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.158

Publications

10 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=-0.57).

BP6

Variant 5-177212104-T-C is Benign according to our data. Variant chr5-177212104-T-C is described in ClinVar as Benign. ClinVar VariationId is 96057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.158 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.3705T>C	p.Asn1235Asn	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.3705T>C	p.Asn1235Asn	synonymous_variant	Exon 5 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15427

AN:

151886

Hom.:

1319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0693

Gnomad ASJ

AF:

0.0559

Gnomad EAS

AF:

0.0174

Gnomad SAS

AF:

0.0866

Gnomad FIN

AF:

0.0275

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.0486

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.0640

AC:

16102

AN:

251432

AF XY:

0.0633

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.0398

Gnomad ASJ exome

AF:

0.0587

Gnomad EAS exome

AF:

0.0191

Gnomad FIN exome

AF:

0.0318

Gnomad NFE exome

AF:

0.0507

Gnomad OTH exome

AF:

0.0671

GnomAD4 exome

AF:

0.0564

AC:

82437

AN:

1461874

Hom.:

3271

Cov.:

AF XY:

0.0572

AC XY:

41577

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.244

AC:

8152

AN:

33478

American (AMR)

AF:

0.0436

AC:

1951

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0584

AC:

1527

AN:

26136

East Asian (EAS)

AF:

0.0171

AC:

679

AN:

39700

South Asian (SAS)

AF:

0.0934

AC:

8059

AN:

86256

European-Finnish (FIN)

AF:

0.0338

AC:

1808

AN:

53420

Middle Eastern (MID)

AF:

0.137

AC:

789

AN:

5768

European-Non Finnish (NFE)

AF:

0.0498

AC:

55366

AN:

1111998

Other (OTH)

AF:

0.0680

AC:

4106

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

4458

8916

13375

17833

22291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2258

4516

6774

9032

11290

<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:

0.102

AC:

15446

AN:

152004

Hom.:

1321

Cov.:

AF XY:

0.0985

AC XY:

7320

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.237

AC:

9806

AN:

41392

American (AMR)

AF:

0.0692

AC:

1056

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0559

AC:

194

AN:

3468

East Asian (EAS)

AF:

0.0174

AC:

AN:

5170

South Asian (SAS)

AF:

0.0869

AC:

419

AN:

4822

European-Finnish (FIN)

AF:

0.0275

AC:

291

AN:

10574

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0487

AC:

3310

AN:

68002

Other (OTH)

AF:

0.106

AC:

225

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

648

1296

1945

2593

3241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0666

Hom.:

333

Bravo

AF:

0.110

Asia WGS

AF:

0.0950

AC:

330

AN:

3478

EpiCase

AF:

0.0516

EpiControl

AF:

0.0540

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

- -

Jun 23, 2014

Eurofins Ntd Llc (ga)

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

- -

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

- -

not provided

Benign:2

Feb 03, 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

Apr 18, 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

-0.57

CADD

Benign

2.0

(source)

DANN

Benign

0.41

PhyloP100

0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=99/1

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