rs3733874

chr5-177210148-G-Achr5-177210148-G-Cchr5-177210148-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022455.5(NSD1):c.1749G>A(p.Glu583=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 96038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210148-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
NSD1	NM_022455.5	c.1749G>A	p.Glu583=	synonymous_variant	5/23	ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.1749G>A	p.Glu583=	synonymous_variant	5/23	1	NM_022455.5	P2

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

GnomAD3 exomes AF: 0.179 AC: 44583 AN: 248928 Hom.: 5628 AF XY: 0.177 AC XY: 23822 AN XY: 134956

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 SAS exome AF: 0.215

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

Gnomad4 AFR exome AF: 0.0744

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.504

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.149

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

Gnomad4 AFR AF: 0.0816

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.507

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.124

Alfa AF: 0.118 Hom.: 566

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

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

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

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	-0.50
Cadd	Benign	5.8
Dann	Benign	0.51

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

Other links and lift over

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