rs78247455

Positions:

chr5-177295004-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 12/20 in silico tools predict 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 made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NSD1. . Gene score misZ 3.4113 (greater than the threshold 3.09). Trascript score misZ 5.7368 (greater than threshold 3.09). GenCC has associacion of gene with Beckwith-Wiedemann syndrome, Weaver syndrome, Sotos syndrome 1, Sotos syndrome.

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/exons	MANE	UniProt
NSD1	NM_022455.5 linkuse as main transcript	c.7636G>A	p.Ala2546Thr	missense_variant	23/23	ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7 linkuse as main transcript	c.7636G>A	p.Ala2546Thr	missense_variant	23/23	1	NM_022455.5	P2	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

GnomAD3 exomes

AF:

0.0238

AC:

5980

AN:

250880

Hom.:

124

AF XY:

0.0254

AC XY:

3448

AN XY:

135828

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 SAS exome

AF:

0.0569

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

Gnomad4 AMR exome

AF:

0.0116

Gnomad4 ASJ exome

AF:

0.00402

Gnomad4 EAS exome

AF:

0.0170

Gnomad4 SAS exome

AF:

0.0537

Gnomad4 FIN exome

AF:

0.0136

Gnomad4 NFE exome

AF:

0.0252

Gnomad4 OTH exome

AF:

0.0273

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

Gnomad4 AMR

AF:

0.0213

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.0171

Gnomad4 SAS

AF:

0.0543

Gnomad4 FIN

AF:

0.0117

Gnomad4 NFE

AF:

0.0231

Gnomad4 OTH

AF:

0.0274

Alfa

AF:

0.0239

Hom.:

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

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28146470) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Sotos syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2022	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2016

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. -

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;.

MutationTaster

Benign

0.63

D;D;N;N

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

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