chr5-177211505-G-C

Variant names:

• chr5-177211505-G-C
• rs28932179
• NM_022455.5:c.3106G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022455.5(NSD1):​c.3106G>C​(p.Ala1036Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,614,082 control chromosomes in the GnomAD database, including 665 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. A1036V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (51 hom., cov: 32)
  • Exomes 𝑓: 0.026 (614 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.392
• Publications: 22 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=0.0053806603).
• BP6: Variant 5-177211505-G-C is Benign according to our data. Variant chr5-177211505-G-C is described in ClinVar as Benign. ClinVar VariationId is 159301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0257 (3919/152256) while in subpopulation AFR AF = 0.03 (1245/41548). AF 95% confidence interval is 0.0286. There are 51 homozygotes in GnomAd4. There are 1867 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3919 AD gene.

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.3106G>C	p.Ala1036Pro	missense	Exon 5 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.3106G>C	p.Ala1036Pro	missense	Exon 5 of 23	NP_001396230.1
	NSD1	NM_001409302.1		c.3106G>C	p.Ala1036Pro	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.3106G>C	p.Ala1036Pro	missense	Exon 5 of 23	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.2233G>C	p.Ala745Pro	missense	Exon 6 of 24	ENSP00000343209.5
	NSD1	ENST00000687453.1		c.2797G>C	p.Ala933Pro	missense	Exon 2 of 20	ENSP00000508426.1

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3920 AN: 152138 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0284

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0227 AC: 5700 AN: 250724 AF XY: 0.0231

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00937

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0264

Gnomad OTH exome AF: 0.0232

GnomAD4 exome AF: 0.0263 AC: 38397 AN: 1461826 Hom.: 614 Cov.: 37 AF XY: 0.0264 AC XY: 19168 AN XY: 727218

African (AFR) AF: 0.0315 AC: 1056 AN: 33480

American (AMR) AF: 0.0102 AC: 456 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 402 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0300 AC: 2589 AN: 86256

European-Finnish (FIN) AF: 0.0310 AC: 1656 AN: 53362

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5768

European-Non Finnish (NFE) AF: 0.0275 AC: 30541 AN: 1112004

Other (OTH) AF: 0.0244 AC: 1471 AN: 60396

GnomAD4 genome AF: 0.0257 AC: 3919 AN: 152256 Hom.: 51 Cov.: 32 AF XY: 0.0251 AC XY: 1867 AN XY: 74450

African (AFR) AF: 0.0300 AC: 1245 AN: 41548

American (AMR) AF: 0.0112 AC: 172 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0274 AC: 132 AN: 4826

European-Finnish (FIN) AF: 0.0303 AC: 321 AN: 10600

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0284 AC: 1932 AN: 68018

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0271 Hom.: 24

Bravo AF: 0.0239

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.0302 AC: 133

ESP6500EA AF: 0.0243 AC: 209

ExAC AF: 0.0236 AC: 2859

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.0279

EpiControl AF: 0.0222

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 07, 2014

Eurofins Ntd Llc (ga)

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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

Mar 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27153395, 27058611)

Sotos syndrome Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Jun 29, 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.89
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.39
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.20	T
Polyphen		0.73	P
Vest4		0.13
MPC		0.067
ClinPred		0.015	T
GERP RS		-7.9
Varity_R		0.11
gMVP		0.28
Mutation Taster		=100/0	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: rs28932179; hg19: chr5-176638506; COSMIC: COSV61770829; COSMIC: COSV61770829;