NM_022455.5:c.2176T>C

Variant names:

• chr5-177210575-T-C
• rs28932178
• NM_022455.5:c.2176T>C

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.2176T>C​(p.Ser726Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,613,816 control chromosomes in the GnomAD database, including 26,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2412 hom., cov: 31)
  • Exomes 𝑓: 0.16 (23746 hom.)
• Consequence: NSD1 NM_022455.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.437
• Publications: 61 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: ClinGen, Orphanet, G2P
• 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=8.151531E-4).
• BP6: Variant 5-177210575-T-C is Benign according to our data. Variant chr5-177210575-T-C is described in ClinVar as Benign. ClinVar VariationId is 96043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.492 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	NM_022455.5	MANE Select	c.2176T>C	p.Ser726Pro	missense	Exon 5 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.2176T>C	p.Ser726Pro	missense	Exon 5 of 23	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.2176T>C	p.Ser726Pro	missense	Exon 5 of 23	NP_001396231.1	Q96L73-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	ENST00000439151.7	TSL:1 MANE Select	c.2176T>C	p.Ser726Pro	missense	Exon 5 of 23	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.1303T>C	p.Ser435Pro	missense	Exon 6 of 24	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000936190.1		c.2176T>C	p.Ser726Pro	missense	Exon 5 of 23	ENSP00000606249.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24486 AN: 151918 Hom.: 2416 Cov.: 31

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.0870

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.202 AC: 50878 AN: 251400 AF XY: 0.201

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.517

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.175

GnomAD4 exome AF: 0.165 AC: 240943 AN: 1461780 Hom.: 23746 Cov.: 38 AF XY: 0.167 AC XY: 121658 AN XY: 727198

African (AFR) AF: 0.0972 AC: 3255 AN: 33480

American (AMR) AF: 0.234 AC: 10469 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3351 AN: 26136

East Asian (EAS) AF: 0.504 AC: 20026 AN: 39698

South Asian (SAS) AF: 0.252 AC: 21711 AN: 86254

European-Finnish (FIN) AF: 0.217 AC: 11578 AN: 53418

Middle Eastern (MID) AF: 0.151 AC: 870 AN: 5768

European-Non Finnish (NFE) AF: 0.143 AC: 159275 AN: 1111910

Other (OTH) AF: 0.172 AC: 10408 AN: 60392

GnomAD4 genome AF: 0.161 AC: 24482 AN: 152036 Hom.: 2412 Cov.: 31 AF XY: 0.169 AC XY: 12545 AN XY: 74300

African (AFR) AF: 0.107 AC: 4423 AN: 41494

American (AMR) AF: 0.181 AC: 2762 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 422 AN: 3468

East Asian (EAS) AF: 0.509 AC: 2622 AN: 5156

South Asian (SAS) AF: 0.278 AC: 1340 AN: 4814

European-Finnish (FIN) AF: 0.219 AC: 2311 AN: 10564

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10192 AN: 67966

Other (OTH) AF: 0.141 AC: 298 AN: 2108

Alfa AF: 0.155 Hom.: 9428

Bravo AF: 0.153

TwinsUK AF: 0.135 AC: 499

ALSPAC AF: 0.133 AC: 512

ESP6500AA AF: 0.103 AC: 452

ESP6500EA AF: 0.138 AC: 1191

ExAC AF: 0.199 AC: 24113

Asia WGS AF: 0.353 AC: 1225 AN: 3478

EpiCase AF: 0.143

EpiControl AF: 0.131

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Sotos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.00082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.44
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.16
Sift	Uncertain	0.013	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.080
MPC		0.066
ClinPred		0.0056	T
GERP RS		1.3
Varity_R		0.093
gMVP		0.36
Mutation Taster		=99/1	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: rs28932178; hg19: chr5-176637576; COSMIC: COSV61770821; COSMIC: COSV61770821;