5-177264278-T-G

Variant names:

• chr5-177264278-T-G
• rs10037055
• NM_022455.5:c.5147-3284T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022455.5(NSD1):​c.5147-3284T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 151,880 control chromosomes in the GnomAD database, including 39,796 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (39796 hom., cov: 30)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.628
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.818 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.5147-3284T>G		intron	N/A	NP_071900.2
	NSD1	NM_001409301.1		c.5147-3284T>G		intron	N/A	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.5147-3284T>G		intron	N/A	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.5147-3284T>G		intron	N/A	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.4274-3284T>G		intron	N/A	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000936190.1		c.5147-3284T>G		intron	N/A	ENSP00000606249.1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107807 AN: 151762 Hom.: 39795 Cov.: 30

Gnomad AFR AF: 0.506

Gnomad AMI AF: 0.902

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.849

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.847

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.753

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.710 AC: 107850 AN: 151880 Hom.: 39796 Cov.: 30 AF XY: 0.707 AC XY: 52452 AN XY: 74238

African (AFR) AF: 0.506 AC: 20946 AN: 41390

American (AMR) AF: 0.758 AC: 11562 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.849 AC: 2949 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2430 AN: 5150

South Asian (SAS) AF: 0.670 AC: 3224 AN: 4814

European-Finnish (FIN) AF: 0.769 AC: 8106 AN: 10538

Middle Eastern (MID) AF: 0.839 AC: 245 AN: 292

European-Non Finnish (NFE) AF: 0.824 AC: 55990 AN: 67964

Other (OTH) AF: 0.751 AC: 1575 AN: 2098

Alfa AF: 0.804 Hom.: 56419

Bravo AF: 0.703

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.5
DANN	Benign	0.33
PhyloP100		0.63
Mutation Taster		=100/0	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: rs10037055; hg19: chr5-176691279; COSMIC: COSV61773319; COSMIC: COSV61773319;