rs78247455

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.7636G>A(p.Ala2546Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,614,198 control chromosomes in the GnomAD database, including 674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 54 hom., cov: 32)

Exomes 𝑓: 0.026 ( 620 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.41

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 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=0.0016538799).

BP6

Variant 5-177295004-G-A is Benign according to our data. Variant chr5-177295004-G-A is described in ClinVar as [Benign]. Clinvar id is 96079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177295004-G-A is described in Lovd as [Benign]. Variant chr5-177295004-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.7636G>A	p.Ala2546Thr	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.7636G>A	p.Ala2546Thr	missense_variant	Exon 23 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3484

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0248

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.0171

Gnomad SAS

AF:

0.0542

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0231

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.0238

AC:

5980

AN:

250880

AF XY:

0.0254

show subpopulations

Gnomad AFR exome

AF:

0.0264

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.0189

Gnomad FIN exome

AF:

0.0126

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0256

AC:

37399

AN:

1461886

Hom.:

620

Cov.:

AF XY:

0.0264

AC XY:

19218

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0254

AC:

850

AN:

33480

Gnomad4 AMR exome

AF:

0.0116

AC:

520

AN:

44724

Gnomad4 ASJ exome

AF:

0.00402

AC:

105

AN:

26136

Gnomad4 EAS exome

AF:

0.0170

AC:

674

AN:

39700

Gnomad4 SAS exome

AF:

0.0537

AC:

4629

AN:

86258

Gnomad4 FIN exome

AF:

0.0136

AC:

726

AN:

53418

Gnomad4 NFE exome

AF:

0.0252

AC:

28073

AN:

1112008

Gnomad4 Remaining exome

AF:

0.0273

AC:

1647

AN:

60396

Heterozygous variant carriers

2426

4852

7279

9705

12131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

1118

2236

3354

4472

5590

<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:

0.0229

AC:

3494

AN:

152312

Hom.:

Cov.:

AF XY:

0.0227

AC XY:

1694

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0248

AC:

0.0247823

AN:

0.0247823

Gnomad4 AMR

AF:

0.0213

AC:

0.0212933

AN:

0.0212933

Gnomad4 ASJ

AF:

0.00403

AC:

0.00403458

AN:

0.00403458

Gnomad4 EAS

AF:

0.0171

AC:

0.0171352

AN:

0.0171352

Gnomad4 SAS

AF:

0.0543

AC:

0.0542668

AN:

0.0542668

Gnomad4 FIN

AF:

0.0117

AC:

0.0116871

AN:

0.0116871

Gnomad4 NFE

AF:

0.0231

AC:

0.0231262

AN:

0.0231262

Gnomad4 OTH

AF:

0.0274

AC:

0.0274361

AN:

0.0274361

Heterozygous variant carriers

170

340

509

679

849

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0240

Hom.:

136

Bravo

AF:

0.0230

TwinsUK

AF:

0.0307

AC:

114

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.0279

AC:

123

ESP6500EA

AF:

0.0237

AC:

204

ExAC

AF:

0.0255

AC:

3095

Asia WGS

AF:

0.0700

AC:

244

AN:

3478

EpiCase

AF:

0.0212

EpiControl

AF:

0.0226

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

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

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

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 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

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

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

0.089

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.082

.;T;.

Eigen

Benign

-0.023

Eigen_PC

Benign

0.029

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

D;D;.

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Uncertain

-0.040

MutationAssessor

Benign

0.90

.;L;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.35

N;N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.079

T;T;T

Polyphen

0.62

P;P;P

Vest4

0.092

MPC

0.14

ClinPred

0.0097

GERP RS

3.8

Varity_R

0.074

gMVP

0.25

Mutation Taster

=100/0

polymorphism (auto)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over