rs28932179

chr5-177211505-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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

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.

• PP2: Missense variant where missense usually causes diseases, NSD1
• 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 id is 159301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177211505-G-C is described in Lovd as [Benign]. Variant chr5-177211505-G-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3920 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5	c.3106G>C	p.Ala1036Pro	missense_variant	5/23	ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.3106G>C	p.Ala1036Pro	missense_variant	5/23	1	NM_022455.5	P2

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

GnomAD3 exomes AF: 0.0227 AC: 5700 AN: 250724 Hom.: 79 AF XY: 0.0231 AC XY: 3126 AN XY: 135610

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 SAS exome AF: 0.0290

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

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.0102

Gnomad4 ASJ exome AF: 0.0154

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0300

Gnomad4 FIN exome AF: 0.0310

Gnomad4 NFE exome AF: 0.0275

Gnomad4 OTH exome AF: 0.0244

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

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0274

Gnomad4 FIN AF: 0.0303

Gnomad4 NFE AF: 0.0284

Gnomad4 OTH AF: 0.0185

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

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -

Sotos syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27153395, 27058611) -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 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. -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.81	T;T;.
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.23	N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.73	P;B;P
Vest4		0.13
MPC		0.067
ClinPred		0.015	T
GERP RS		-7.9
Varity_R		0.11
gMVP		0.28

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: rs28932179; hg19: chr5-176638506; COSMIC: COSV61770829; COSMIC: COSV61770829;