NM_022455.5:c.4498-10delT

Variant names:

• chr5-177248165-AT-A
• rs200890017
• NM_022455.5:c.4498-10delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_022455.5(NSD1):​c.4498-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,718 control chromosomes in the GnomAD database, including 534 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 32)
  • Exomes 𝑓: 0.023 (503 hom.)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.52
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 5-177248165-AT-A is Benign according to our data. Variant chr5-177248165-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0168 (2550/152224) while in subpopulation NFE AF = 0.0273 (1855/68020). AF 95% confidence interval is 0.0262. There are 31 homozygotes in GnomAd4. There are 1212 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2550 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.4498-10delT		intron	N/A	NP_071900.2
	NSD1	NM_001409301.1		c.4498-10delT		intron	N/A	NP_001396230.1
	NSD1	NM_001409302.1		c.4498-10delT		intron	N/A	NP_001396231.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSD1	ENST00000439151.7	TSL:1 MANE Select	c.4498-15delT		intron	N/A	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.3625-15delT		intron	N/A	ENSP00000343209.5
	NSD1	ENST00000687453.1		c.4189-15delT		intron	N/A	ENSP00000508426.1

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2553 AN: 152106 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.00961

GnomAD2 exomes AF: 0.0169 AC: 4237 AN: 250542 AF XY: 0.0170

Gnomad AFR exome AF: 0.00463

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.0233 AC: 34034 AN: 1461494 Hom.: 503 Cov.: 32 AF XY: 0.0230 AC XY: 16696 AN XY: 727004

African (AFR) AF: 0.00329 AC: 110 AN: 33472

American (AMR) AF: 0.00677 AC: 302 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0114 AC: 982 AN: 86186

European-Finnish (FIN) AF: 0.0307 AC: 1640 AN: 53338

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5766

European-Non Finnish (NFE) AF: 0.0268 AC: 29789 AN: 1111878

Other (OTH) AF: 0.0178 AC: 1073 AN: 60386

GnomAD4 genome AF: 0.0168 AC: 2550 AN: 152224 Hom.: 31 Cov.: 32 AF XY: 0.0163 AC XY: 1212 AN XY: 74422

African (AFR) AF: 0.00390 AC: 162 AN: 41530

American (AMR) AF: 0.00778 AC: 119 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4824

European-Finnish (FIN) AF: 0.0300 AC: 318 AN: 10600

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0273 AC: 1855 AN: 68020

Other (OTH) AF: 0.00951 AC: 20 AN: 2104

Alfa AF: 0.0138 Hom.: 7

Bravo AF: 0.0140

Asia WGS AF: 0.00491 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

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

Apr 30, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 04, 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

Sotos syndrome Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200890017; hg19: chr5-176675166;