rs35848863

Positions:

Variant summary

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

The NM_022455.5(NSD1):c.6750G>A(p.Met2250Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0516 in 1,614,000 control chromosomes in the GnomAD database, including 2,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 199 hom., cov: 30)

Exomes 𝑓: 0.052 ( 2308 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0770

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=0.0012430251).

BP6

Variant 5-177294118-G-A is Benign according to our data. Variant chr5-177294118-G-A is described in ClinVar as [Benign]. Clinvar id is 96070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177294118-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.075 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.6750G>A	p.Met2250Ile	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.6750G>A	p.Met2250Ile	missense_variant	23/23	1	NM_022455.5	P2	Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.0487

AC:

7401

AN:

152058

Hom.:

198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0549

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0326

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.0177

Gnomad SAS

AF:

0.0818

Gnomad FIN

AF:

0.0418

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0515

Gnomad OTH

AF:

0.0436

GnomAD3 exomes

AF:

0.0467

AC:

11724

AN:

251202

Hom.:

351

AF XY:

0.0485

AC XY:

6583

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.0592

Gnomad AMR exome

AF:

0.0198

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.0191

Gnomad SAS exome

AF:

0.0859

Gnomad FIN exome

AF:

0.0434

Gnomad NFE exome

AF:

0.0501

Gnomad OTH exome

AF:

0.0466

GnomAD4 exome

AF:

0.0519

AC:

75817

AN:

1461824

Hom.:

2308

Cov.:

AF XY:

0.0528

AC XY:

38398

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0570

Gnomad4 AMR exome

AF:

0.0218

Gnomad4 ASJ exome

AF:

0.0194

Gnomad4 EAS exome

AF:

0.0173

Gnomad4 SAS exome

AF:

0.0837

Gnomad4 FIN exome

AF:

0.0446

Gnomad4 NFE exome

AF:

0.0527

Gnomad4 OTH exome

AF:

0.0516

GnomAD4 genome

AF:

0.0487

AC:

7410

AN:

152176

Hom.:

199

Cov.:

AF XY:

0.0478

AC XY:

3556

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0549

Gnomad4 AMR

AF:

0.0326

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.0178

Gnomad4 SAS

AF:

0.0816

Gnomad4 FIN

AF:

0.0418

Gnomad4 NFE

AF:

0.0515

Gnomad4 OTH

AF:

0.0460

Alfa

AF:

0.0481

Hom.:

358

Bravo

AF:

0.0469

TwinsUK

AF:

0.0580

AC:

215

ALSPAC

AF:

0.0498

AC:

192

ESP6500AA

AF:

0.0590

AC:

260

ESP6500EA

AF:

0.0488

AC:

420

ExAC

AF:

0.0492

AC:

5970

Asia WGS

AF:

0.0930

AC:

324

AN:

3478

EpiCase

AF:

0.0491

EpiControl

AF:

0.0449

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 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	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	Invitae	Nov 03, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.067

.;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.71

T;T;.

MetaRNN

Benign

0.0012

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.73

N;N;N

REVEL

Benign

0.066

Sift

Benign

0.043

D;D;D

Sift4G

Benign

0.17

T;T;T

Polyphen

0.095

B;B;B

Vest4

0.11

MutPred

0.057

.;Loss of catalytic residue at M2250 (P = 0.0214);.;

MPC

0.16

ClinPred

0.0019

GERP RS

1.5

Varity_R

0.070

gMVP

0.12

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