rs78247455

chr5-177295004-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_022455.5(NSD1):c.7636G>A(p.Ala2546Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,614,198 control chromosomes in the GnomAD database, including 674 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (54 hom., cov: 32)
  • Exomes 𝑓: 0.026 (620 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.41

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=0.0016538799).
• BP6: Variant 5-177295004-G-A is Benign according to our data. Variant chr5-177295004-G-A is described in ClinVar as [Benign]. Clinvar id is 96079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177295004-G-A is described in Lovd as [Benign]. Variant chr5-177295004-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSD1	NM_022455.5	c.7636G>A	p.Ala2546Thr	missense_variant	23/23	ENST00000439151.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSD1	ENST00000439151.7	c.7636G>A	p.Ala2546Thr	missense_variant	23/23	1	NM_022455.5	P2

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3484 AN: 152194 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.0542

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0238 AC: 5980 AN: 250880 Hom.: 124 AF XY: 0.0254 AC XY: 3448 AN XY: 135828

Gnomad AFR exome AF: 0.0264

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.0189

Gnomad SAS exome AF: 0.0569

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0256 AC: 37399 AN: 1461886 Hom.: 620 Cov.: 34 AF XY: 0.0264 AC XY: 19218 AN XY: 727244

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.0170

Gnomad4 SAS exome AF: 0.0537

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0273

GnomAD4 genome AF: 0.0229 AC: 3494 AN: 152312 Hom.: 54 Cov.: 32 AF XY: 0.0227 AC XY: 1694 AN XY: 74492

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.0171

Gnomad4 SAS AF: 0.0543

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0239 Hom.: 87

Bravo AF: 0.0230

TwinsUK AF: 0.0307 AC: 114

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.0237 AC: 204

ExAC AF: 0.0255 AC: 3095

Asia WGS AF: 0.0700 AC: 244 AN: 3478

EpiCase AF: 0.0212

EpiControl AF: 0.0226

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

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, 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+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28146470) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Sotos syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2022	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 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	-0.39	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.023
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;D;.
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Uncertain	-0.040	T
MutationTaster	Benign	0.63	D;D;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.079	T;T;T
Polyphen		0.62	P;P;P
Vest4		0.092
MPC		0.14
ClinPred		0.0097	T
GERP RS		3.8
Varity_R		0.074
gMVP		0.25

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: rs78247455; hg19: chr5-176722005;