rs28932176

Positions:

chr5-177210191-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022455.5(NSD1):c.1792T>C(p.Leu598=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00829 in 1,600,966 control chromosomes in the GnomAD database, including 245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 234 hom. )

Consequence

NSD1
NM_022455.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.33

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 5-177210191-T-C is Benign according to our data. Variant chr5-177210191-T-C is described in ClinVar as [Benign]. Clinvar id is 96040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210191-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2.33 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0504 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.1792T>C	p.Leu598=	synonymous_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.1792T>C	p.Leu598=	synonymous_variant	5/23	1	NM_022455.5	ENSP00000395929	P2	Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.00641

AC:

976

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.0444

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0518

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00638

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.0121

AC:

2877

AN:

238398

Hom.:

AF XY:

0.0144

AC XY:

1859

AN XY:

129328

show subpopulations

Gnomad AFR exome

AF:

0.000780

Gnomad AMR exome

AF:

0.00378

Gnomad ASJ exome

AF:

0.0444

Gnomad EAS exome

AF:

0.000170

Gnomad SAS exome

AF:

0.0542

Gnomad FIN exome

AF:

0.00104

Gnomad NFE exome

AF:

0.00660

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.00849

AC:

12297

AN:

1448688

Hom.:

234

Cov.:

AF XY:

0.00983

AC XY:

7076

AN XY:

719718

show subpopulations

Gnomad4 AFR exome

AF:

0.00101

Gnomad4 AMR exome

AF:

0.00379

Gnomad4 ASJ exome

AF:

0.0426

Gnomad4 EAS exome

AF:

0.0000759

Gnomad4 SAS exome

AF:

0.0517

Gnomad4 FIN exome

AF:

0.00104

Gnomad4 NFE exome

AF:

0.00522

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.00638

AC:

972

AN:

152278

Hom.:

Cov.:

AF XY:

0.00628

AC XY:

468

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.0444

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0510

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00638

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00818

Hom.:

Bravo

AF:

0.00509

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 22, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Sotos syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -
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

Jun 14, 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

-0.57

CADD

Benign

9.2

DANN

Benign

0.66

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