chr5-177210239-G-T

Position:

chr5-177210239-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_022455.5(NSD1):c.1840G>T(p.Val614Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,597,604 control chromosomes in the GnomAD database, including 19,804 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1923 hom., cov: 31)

Exomes 𝑓: 0.14 ( 17881 hom. )

Consequence

NSD1
NM_022455.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.285

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.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NSD1. . Gene score misZ 3.4113 (greater than the threshold 3.09). Trascript score misZ 5.7368 (greater than threshold 3.09). GenCC has associacion of gene with Beckwith-Wiedemann syndrome, Weaver syndrome, Sotos syndrome 1, Sotos syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=9.2281436E-5).

BP6

Variant 5-177210239-G-T is Benign according to our data. Variant chr5-177210239-G-T is described in ClinVar as [Benign]. Clinvar id is 96042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177210239-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 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.1840G>T	p.Val614Leu	missense_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.1840G>T	p.Val614Leu	missense_variant	5/23	1	NM_022455.5	ENSP00000395929.2		Q96L73-1

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20563

AN:

151934

Hom.:

1926

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0764

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.510

Gnomad SAS

AF:

0.248

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.122

GnomAD3 exomes

AF:

0.179

AC:

42796

AN:

239304

Hom.:

5414

AF XY:

0.176

AC XY:

22851

AN XY:

129698

show subpopulations

Gnomad AFR exome

AF:

0.0748

Gnomad AMR exome

AF:

0.235

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.517

Gnomad SAS exome

AF:

0.215

Gnomad FIN exome

AF:

0.184

Gnomad NFE exome

AF:

0.118

Gnomad OTH exome

AF:

0.154

GnomAD4 exome

AF:

0.138

AC:

199439

AN:

1445552

Hom.:

17881

Cov.:

AF XY:

0.140

AC XY:

100517

AN XY:

717724

show subpopulations

Gnomad4 AFR exome

AF:

0.0681

Gnomad4 AMR exome

AF:

0.222

Gnomad4 ASJ exome

AF:

0.113

Gnomad4 EAS exome

AF:

0.504

Gnomad4 SAS exome

AF:

0.217

Gnomad4 FIN exome

AF:

0.185

Gnomad4 NFE exome

AF:

0.116

Gnomad4 OTH exome

AF:

0.149

GnomAD4 genome

AF:

0.135

AC:

20564

AN:

152052

Hom.:

1923

Cov.:

AF XY:

0.143

AC XY:

10662

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0762

Gnomad4 AMR

AF:

0.170

Gnomad4 ASJ

AF:

0.112

Gnomad4 EAS

AF:

0.510

Gnomad4 SAS

AF:

0.248

Gnomad4 FIN

AF:

0.188

Gnomad4 NFE

AF:

0.122

Gnomad4 OTH

AF:

0.123

Alfa

AF:

0.126

Hom.:

3798

Bravo

AF:

0.130

TwinsUK

AF:

0.107

AC:

398

ALSPAC

AF:

0.108

AC:

417

ESP6500AA

AF:

0.0704

AC:

310

ESP6500EA

AF:

0.114

AC:

982

ExAC

AF:

0.174

AC:

21135

Asia WGS

AF:

0.332

AC:

1151

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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)	Jun 10, 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.0070

DANN

Benign

0.53

DEOGEN2

Benign

0.060

.;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.64

T;T;.

MetaRNN

Benign

0.000092

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.26

.;N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.47

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.91

T;T;T

Polyphen

0.0020

B;B;B

Vest4

0.14

MutPred

0.14

.;Loss of MoRF binding (P = 0.0946);.;

MPC

0.054

ClinPred

0.0017

GERP RS

-1.3

Varity_R

0.024

gMVP

0.16

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