rs28932177

Positions:

chr5-177210470-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_022455.5(NSD1):c.2071G>A(p.Ala691Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,614,110 control chromosomes in the GnomAD database, including 608 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A691A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 32 hom., cov: 32)

Exomes 𝑓: 0.025 ( 576 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.462

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=0.0032784045).

BP6

Variant 5-177210470-G-A is Benign according to our data. Variant chr5-177210470-G-A is described in ClinVar as [Benign]. Clinvar id is 159279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210470-G-A is described in Lovd as [Benign]. Variant chr5-177210470-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0182 (2778/152266) while in subpopulation NFE AF= 0.0282 (1919/68008). AF 95% confidence interval is 0.0272. There are 32 homozygotes in gnomad4. There are 1334 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2778 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5 linkuse as main transcript	c.2071G>A	p.Ala691Thr	missense_variant	5/23	ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7 linkuse as main transcript	c.2071G>A	p.Ala691Thr	missense_variant	5/23	1	NM_022455.5	P2	Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2781

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00444

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00831

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0302

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0282

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0205

AC:

5162

AN:

251228

Hom.:

AF XY:

0.0215

AC XY:

2919

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00501

Gnomad AMR exome

AF:

0.00766

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0289

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0253

AC:

36996

AN:

1461844

Hom.:

576

Cov.:

AF XY:

0.0255

AC XY:

18578

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00349

Gnomad4 AMR exome

AF:

0.00821

Gnomad4 ASJ exome

AF:

0.0142

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0299

Gnomad4 FIN exome

AF:

0.0310

Gnomad4 NFE exome

AF:

0.0274

Gnomad4 OTH exome

AF:

0.0212

GnomAD4 genome

AF:

0.0182

AC:

2778

AN:

152266

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1334

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00443

Gnomad4 AMR

AF:

0.00830

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0267

Gnomad4 FIN

AF:

0.0302

Gnomad4 NFE

AF:

0.0282

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0241

Hom.:

Bravo

AF:

0.0151

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0244

AC:

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.0241

AC:

207

ExAC

AF:

0.0209

AC:

2534

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0276

EpiControl

AF:

0.0219

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 25, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	Invitae	Nov 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 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

0.066

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.052

.;T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.80

T;T;.

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.2

.;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.22

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.0060

B;B;B

Vest4

0.056

MPC

0.054

ClinPred

0.0027

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.028

gMVP

0.14

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