rs3733874

Variant names:

• chr5-177210148-G-A
• rs3733874
• NM_022455.5:c.1749G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-177210148-G-A
• chr5-177210148-G-C
• chr5-177210148-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022455.5(NSD1):​c.1749G>A​(p.Glu583Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.138 in 1,612,332 control chromosomes in the GnomAD database, including 20,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1927 hom., cov: 31)
  • Exomes 𝑓: 0.14 (18162 hom.)
• Consequence: NSD1 NM_022455.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.71
• Publications: 28 publications found

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 Gene-Disease associations (from GenCC):

• Beckwith-Wiedemann syndrome due to NSD1 mutation

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Sotos syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• Sotos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 5-177210148-G-A is Benign according to our data. Variant chr5-177210148-G-A is described in ClinVar as Benign. ClinVar VariationId is 96038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.491 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5	c.1749G>A	p.Glu583Glu	synonymous_variant	Exon 5 of 23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.1749G>A	p.Glu583Glu	synonymous_variant	Exon 5 of 23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20788 AN: 152004 Hom.: 1930 Cov.: 31

Gnomad AFR AF: 0.0818

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.179 AC: 44583 AN: 248928 AF XY: 0.177

Gnomad AFR exome AF: 0.0801

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.516

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.138 AC: 202175 AN: 1460210 Hom.: 18162 Cov.: 38 AF XY: 0.141 AC XY: 102108 AN XY: 726312

African (AFR) AF: 0.0744 AC: 2485 AN: 33412

American (AMR) AF: 0.223 AC: 9871 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2962 AN: 26044

East Asian (EAS) AF: 0.504 AC: 19992 AN: 39674

South Asian (SAS) AF: 0.217 AC: 18642 AN: 85888

European-Finnish (FIN) AF: 0.186 AC: 9911 AN: 53390

Middle Eastern (MID) AF: 0.117 AC: 672 AN: 5764

European-Non Finnish (NFE) AF: 0.116 AC: 128640 AN: 1111408

Other (OTH) AF: 0.149 AC: 9000 AN: 60310

GnomAD4 genome AF: 0.137 AC: 20788 AN: 152122 Hom.: 1927 Cov.: 31 AF XY: 0.145 AC XY: 10776 AN XY: 74356

African (AFR) AF: 0.0816 AC: 3387 AN: 41510

American (AMR) AF: 0.170 AC: 2603 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 390 AN: 3466

East Asian (EAS) AF: 0.507 AC: 2617 AN: 5158

South Asian (SAS) AF: 0.249 AC: 1203 AN: 4826

European-Finnish (FIN) AF: 0.188 AC: 1987 AN: 10584

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8262 AN: 67988

Other (OTH) AF: 0.124 AC: 261 AN: 2112

Alfa AF: 0.117 Hom.: 567

Bravo AF: 0.132

Asia WGS AF: 0.332 AC: 1151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 10, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 19, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sotos syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.8
DANN	Benign	0.51
PhyloP100		3.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3733874; hg19: chr5-176637149; COSMIC: COSV61771201; COSMIC: COSV61771201;