5-177210575-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_022455.5(NSD1):c.2176T>C(p.Ser726Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,613,816 control chromosomes in the GnomAD database, including 26,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2412 hom., cov: 31)

Exomes 𝑓: 0.16 ( 23746 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.437

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 made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the NSD1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 153 curated benign missense variants. Gene score misZ: 3.4113 (above the threshold of 3.09). Trascript score misZ: 5.7368 (above the threshold of 3.09). GenCC associations: The gene is linked to Beckwith-Wiedemann syndrome, Weaver syndrome, Sotos syndrome 1, Sotos syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=8.151531E-4).

BP6

Variant 5-177210575-T-C is Benign according to our data. Variant chr5-177210575-T-C is described in ClinVar as [Benign]. Clinvar id is 96043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210575-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.492 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5 link	c.2176T>C	p.Ser726Pro	missense_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.2176T>C	p.Ser726Pro	missense_variant	Exon 5 of 23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24486

AN:

151918

Hom.:

2416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.0870

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.509

Gnomad SAS

AF:

0.278

Gnomad FIN

AF:

0.219

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.150

Gnomad OTH

AF:

0.141

GnomAD3 exomes

AF:

0.202

AC:

50878

AN:

251400

Hom.:

6607

AF XY:

0.201

AC XY:

27284

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.245

Gnomad ASJ exome

AF:

0.127

Gnomad EAS exome

AF:

0.517

Gnomad SAS exome

AF:

0.250

Gnomad FIN exome

AF:

0.216

Gnomad NFE exome

AF:

0.145

Gnomad OTH exome

AF:

0.175

GnomAD4 exome

AF:

0.165

AC:

240943

AN:

1461780

Hom.:

23746

Cov.:

AF XY:

0.167

AC XY:

121658

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0972

Gnomad4 AMR exome

AF:

0.234

Gnomad4 ASJ exome

AF:

0.128

Gnomad4 EAS exome

AF:

0.504

Gnomad4 SAS exome

AF:

0.252

Gnomad4 FIN exome

AF:

0.217

Gnomad4 NFE exome

AF:

0.143

Gnomad4 OTH exome

AF:

0.172

GnomAD4 genome

AF:

0.161

AC:

24482

AN:

152036

Hom.:

2412

Cov.:

AF XY:

0.169

AC XY:

12545

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.107

Gnomad4 AMR

AF:

0.181

Gnomad4 ASJ

AF:

0.122

Gnomad4 EAS

AF:

0.509

Gnomad4 SAS

AF:

0.278

Gnomad4 FIN

AF:

0.219

Gnomad4 NFE

AF:

0.150

Gnomad4 OTH

AF:

0.141

Alfa

AF:

0.153

Hom.:

4706

Bravo

AF:

0.153

TwinsUK

AF:

0.135

AC:

499

ALSPAC

AF:

0.133

AC:

512

ESP6500AA

AF:

0.103

AC:

452

ESP6500EA

AF:

0.138

AC:

1191

ExAC

AF:

0.199

AC:

24113

Asia WGS

AF:

0.353

AC:

1225

AN:

3478

EpiCase

AF:

0.143

EpiControl

AF:

0.131

ClinVar

Significance: Benign

Submissions summary: Benign:10

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

- -

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Jun 10, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Feb 04, 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: 29083408) -

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

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.073

.;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.59

T;T;.

MetaRNN

Benign

0.00082

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

.;M;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.99

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.013

D;D;D

Sift4G

Benign

0.15

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.080

MPC

0.066

ClinPred

0.0056

GERP RS

1.3

Varity_R

0.093

gMVP

0.36

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