rs1363405

Positions:

chr5-177209881-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_022455.5(NSD1):c.1482C>T(p.Cys494Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,613,566 control chromosomes in the GnomAD database, including 60,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 13160 hom., cov: 31)

Exomes 𝑓: 0.23 ( 47004 hom. )

Consequence

NSD1
NM_022455.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.98

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:

NSD1 (HGNC:):

NSD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 5-177209881-C-T is Benign according to our data. Variant chr5-177209881-C-T is described in ClinVar as [Benign]. Clinvar id is 96035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177209881-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.98 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSD1	NM_022455.5 linkuse as main transcript	c.1482C>T	p.Cys494Cys	synonymous_variant	5/23	ENST00000439151.7	NP_071900.2	Q96L73-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7 linkuse as main transcript	c.1482C>T	p.Cys494Cys	synonymous_variant	5/23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.360

AC:

54694

AN:

151792

Hom.:

13139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.681

Gnomad AMI

AF:

0.0989

Gnomad AMR

AF:

0.285

Gnomad ASJ

AF:

0.201

Gnomad EAS

AF:

0.528

Gnomad SAS

AF:

0.364

Gnomad FIN

AF:

0.247

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.315

GnomAD3 exomes

AF:

0.293

AC:

73412

AN:

250886

Hom.:

13403

AF XY:

0.283

AC XY:

38429

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.696

Gnomad AMR exome

AF:

0.301

Gnomad ASJ exome

AF:

0.205

Gnomad EAS exome

AF:

0.537

Gnomad SAS exome

AF:

0.341

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.198

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.232

AC:

339226

AN:

1461656

Hom.:

47004

Cov.:

AF XY:

0.234

AC XY:

170003

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.693

Gnomad4 AMR exome

AF:

0.297

Gnomad4 ASJ exome

AF:

0.207

Gnomad4 EAS exome

AF:

0.522

Gnomad4 SAS exome

AF:

0.342

Gnomad4 FIN exome

AF:

0.251

Gnomad4 NFE exome

AF:

0.194

Gnomad4 OTH exome

AF:

0.267

GnomAD4 genome

AF:

0.361

AC:

54774

AN:

151910

Hom.:

13160

Cov.:

AF XY:

0.362

AC XY:

26848

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.681

Gnomad4 AMR

AF:

0.285

Gnomad4 ASJ

AF:

0.201

Gnomad4 EAS

AF:

0.527

Gnomad4 SAS

AF:

0.364

Gnomad4 FIN

AF:

0.247

Gnomad4 NFE

AF:

0.200

Gnomad4 OTH

AF:

0.316

Alfa

AF:

0.237

Hom.:

7145

Bravo

AF:

0.375

Asia WGS

AF:

0.473

AC:

1640

AN:

3478

EpiCase

AF:

0.196

EpiControl

AF:

0.187

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-	- -
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+	-	- -

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	Nov 03, 2022	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 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

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.68

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