rs28932179

Positions:

chr5-177211505-G-C

Variant summary

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

The NM_022455.5(NSD1):c.3106G>C(p.Ala1036Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,614,082 control chromosomes in the GnomAD database, including 665 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 0.026 ( 51 hom., cov: 32)

Exomes 𝑓: 0.026 ( 614 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.392

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=0.0053806603).

BP6

Variant 5-177211505-G-C is Benign according to our data. Variant chr5-177211505-G-C is described in ClinVar as [Benign]. Clinvar id is 159301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177211505-G-C is described in Lovd as [Benign]. Variant chr5-177211505-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0257 (3919/152256) while in subpopulation AFR AF= 0.03 (1245/41548). AF 95% confidence interval is 0.0286. There are 51 homozygotes in gnomad4. There are 1867 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3919 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD1	NM_022455.5 linkuse as main transcript	c.3106G>C	p.Ala1036Pro	missense_variant	5/23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7 linkuse as main transcript	c.3106G>C	p.Ala1036Pro	missense_variant	5/23	1	NM_022455.5	ENSP00000395929	P2	Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.0258

AC:

3920

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0300

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0303

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0284

Gnomad OTH

AF:

0.0187

GnomAD3 exomes

AF:

0.0227

AC:

5700

AN:

250724

Hom.:

AF XY:

0.0231

AC XY:

3126

AN XY:

135610

show subpopulations

Gnomad AFR exome

AF:

0.0328

Gnomad AMR exome

AF:

0.00937

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0290

Gnomad FIN exome

AF:

0.0309

Gnomad NFE exome

AF:

0.0264

Gnomad OTH exome

AF:

0.0232

GnomAD4 exome

AF:

0.0263

AC:

38397

AN:

1461826

Hom.:

614

Cov.:

AF XY:

0.0264

AC XY:

19168

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0315

Gnomad4 AMR exome

AF:

0.0102

Gnomad4 ASJ exome

AF:

0.0154

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0300

Gnomad4 FIN exome

AF:

0.0310

Gnomad4 NFE exome

AF:

0.0275

Gnomad4 OTH exome

AF:

0.0244

GnomAD4 genome

AF:

0.0257

AC:

3919

AN:

152256

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

1867

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0300

Gnomad4 AMR

AF:

0.0112

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.0274

Gnomad4 FIN

AF:

0.0303

Gnomad4 NFE

AF:

0.0284

Gnomad4 OTH

AF:

0.0185

Alfa

AF:

0.0271

Hom.:

Bravo

AF:

0.0239

TwinsUK

AF:

0.0270

AC:

100

ALSPAC

AF:

0.0244

AC:

ESP6500AA

AF:

0.0302

AC:

133

ESP6500EA

AF:

0.0243

AC:

209

ExAC

AF:

0.0236

AC:

2859

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0279

EpiControl

AF:

0.0222

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Sotos syndrome

Benign:3

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	Nov 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27153395, 27058611) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

0.089

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.087

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.81

T;T;.

MetaRNN

Benign

0.0054

T;T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.0

.;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

0.23

N;N;N

REVEL

Benign

0.25

Sift

Uncertain

0.0020

D;D;D

Sift4G

Benign

0.20

T;T;T

Polyphen

0.73

P;B;P

Vest4

0.13

MPC

0.067

ClinPred

0.015

GERP RS

-7.9

Varity_R

0.11

gMVP

0.28

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