5-177210239-G-T

Variant names:

• chr5-177210239-G-T
• rs3733875
• NM_022455.5:c.1840G>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.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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V614M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1923 hom., cov: 31)
  • Exomes 𝑓: 0.14 (17881 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.285
• Publications: 58 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 (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 VariationId is 96042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	NM_022455.5	MANE Select	c.1840G>T	p.Val614Leu	missense	Exon 5 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.1840G>T	p.Val614Leu	missense	Exon 5 of 23	NP_001396230.1
	NSD1	NM_001409302.1		c.1840G>T	p.Val614Leu	missense	Exon 5 of 23	NP_001396231.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	ENST00000439151.7	TSL:1 MANE Select	c.1840G>T	p.Val614Leu	missense	Exon 5 of 23	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.967G>T	p.Val323Leu	missense	Exon 6 of 24	ENSP00000343209.5
	NSD1	ENST00000687453.1		c.1531G>T	p.Val511Leu	missense	Exon 2 of 20	ENSP00000508426.1

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20563 AN: 151934 Hom.: 1926 Cov.: 31

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

GnomAD2 exomes AF: 0.179 AC: 42796 AN: 239304 AF XY: 0.176

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 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.: 38 AF XY: 0.140 AC XY: 100517 AN XY: 717724

African (AFR) AF: 0.0681 AC: 2228 AN: 32718

American (AMR) AF: 0.222 AC: 9307 AN: 41956

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2861 AN: 25208

East Asian (EAS) AF: 0.504 AC: 19906 AN: 39504

South Asian (SAS) AF: 0.217 AC: 18176 AN: 83920

European-Finnish (FIN) AF: 0.185 AC: 9817 AN: 52932

Middle Eastern (MID) AF: 0.117 AC: 660 AN: 5662

European-Non Finnish (NFE) AF: 0.116 AC: 127646 AN: 1104158

Other (OTH) AF: 0.149 AC: 8838 AN: 59494

GnomAD4 genome AF: 0.135 AC: 20564 AN: 152052 Hom.: 1923 Cov.: 31 AF XY: 0.143 AC XY: 10662 AN XY: 74314

African (AFR) AF: 0.0762 AC: 3160 AN: 41486

American (AMR) AF: 0.170 AC: 2598 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 390 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2619 AN: 5140

South Asian (SAS) AF: 0.248 AC: 1197 AN: 4818

European-Finnish (FIN) AF: 0.188 AC: 1994 AN: 10584

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8269 AN: 67978

Other (OTH) AF: 0.123 AC: 260 AN: 2112

Alfa AF: 0.128 Hom.: 7185

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

Submissions by phenotype

not specified Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.58	T
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	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.000092	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.26	N
PhyloP100		-0.28
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.19
Sift	Benign	0.32	T
Sift4G	Benign	0.91	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.14		Loss of MoRF binding (P = 0.0946)
MPC		0.054
ClinPred		0.0017	T
GERP RS		-1.3
Varity_R		0.024
gMVP		0.16
Mutation Taster		=96/4	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: rs3733875; hg19: chr5-176637240; COSMIC: COSV61771212; COSMIC: COSV61771212;