5-177210089-G-T

Variant names:

• chr5-177210089-G-T
• rs116520623
• NM_022455.5:c.1690G>T

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.1690G>T​(p.Ala564Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000945 in 1,613,450 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (10 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0270
• Publications: 8 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=0.0036613941).
• BP6: Variant 5-177210089-G-T is Benign according to our data. Variant chr5-177210089-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159270.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 = 0.00423 (644/152260) while in subpopulation AFR AF = 0.0142 (588/41548). AF 95% confidence interval is 0.0132. There are 3 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 644 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.1690G>T	p.Ala564Ser	missense	Exon 5 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.1690G>T	p.Ala564Ser	missense	Exon 5 of 23	NP_001396230.1
	NSD1	NM_001409302.1		c.1690G>T	p.Ala564Ser	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.1690G>T	p.Ala564Ser	missense	Exon 5 of 23	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.817G>T	p.Ala273Ser	missense	Exon 6 of 24	ENSP00000343209.5
	NSD1	ENST00000687453.1		c.1381G>T	p.Ala461Ser	missense	Exon 2 of 20	ENSP00000508426.1

Frequencies

GnomAD3 genomes AF: 0.00421 AC: 641 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00142 AC: 355 AN: 250092 AF XY: 0.00110

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000987

GnomAD4 exome AF: 0.000603 AC: 881 AN: 1461190 Hom.: 10 Cov.: 37 AF XY: 0.000512 AC XY: 372 AN XY: 726832

African (AFR) AF: 0.0165 AC: 553 AN: 33448

American (AMR) AF: 0.00128 AC: 57 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5760

European-Non Finnish (NFE) AF: 0.0000845 AC: 94 AN: 1111772

Other (OTH) AF: 0.00194 AC: 117 AN: 60358

GnomAD4 genome AF: 0.00423 AC: 644 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74434

African (AFR) AF: 0.0142 AC: 588 AN: 41548

American (AMR) AF: 0.00216 AC: 33 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000981 Hom.: 4

Bravo AF: 0.00473

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sotos syndrome Benign:3

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 17, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Aug 03, 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	0.077
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	2.9
DANN	Benign	0.95
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.027
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.12	T
Polyphen		0.40	B
Vest4		0.10
MVP		0.34
MPC		0.052
ClinPred		0.0030	T
GERP RS		-1.2
Varity_R		0.035
gMVP		0.28
Mutation Taster		=98/2	polymorphism

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: rs116520623; hg19: chr5-176637090;