rs1363405

chr5-177209881-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_022455.5(NSD1):c.1482C>T(p.Cys494=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.98

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 -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	UniProt
NSD1	NM_022455.5	c.1482C>T	p.Cys494=	synonymous_variant	5/23	ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.1482C>T	p.Cys494=	synonymous_variant	5/23	1	NM_022455.5	P2

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54694 AN: 151792 Hom.: 13139 Cov.: 31

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

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.: 40 AF XY: 0.234 AC XY: 170003 AN XY: 727142

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.: 31 AF XY: 0.362 AC XY: 26848 AN XY: 74228

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

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 10, 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	-0.46
Cadd	Benign	11
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

Other links and lift over

dbSNP: rs1363405; hg19: chr5-176636882; COSMIC: COSV61770800; COSMIC: COSV61770800;