rs3733873

Variant names:

• chr5-177134112-T-C
• rs3733873
• NM_022455.5:c.-18+160T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022455.5(NSD1):​c.-18+160T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 148,406 control chromosomes in the GnomAD database, including 11,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (11506 hom., cov: 28)
  • Exomes 𝑓: 0.21 (1 hom.)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.158
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-177134112-T-C is Benign according to our data. Variant chr5-177134112-T-C is described in ClinVar as [Benign]. Clinvar id is 1239366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5	c.-18+160T>C		intron_variant	Intron 1 of 22	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.-18+160T>C		intron_variant	Intron 1 of 22	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes AF: 0.333 AC: 49435 AN: 148264 Hom.: 11486 Cov.: 28

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.0767

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.291

GnomAD4 exome AF: 0.214 AC: 9 AN: 42 Hom.: 1 Cov.: 0 AF XY: 0.225 AC XY: 9 AN XY: 40

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.194 AC: 7 AN: 36

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.334 AC: 49498 AN: 148364 Hom.: 11506 Cov.: 28 AF XY: 0.335 AC XY: 24284 AN XY: 72436

African (AFR) AF: 0.655 AC: 26389 AN: 40260

American (AMR) AF: 0.263 AC: 3970 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 676 AN: 3450

East Asian (EAS) AF: 0.504 AC: 2368 AN: 4696

South Asian (SAS) AF: 0.307 AC: 1427 AN: 4654

European-Finnish (FIN) AF: 0.227 AC: 2286 AN: 10090

Middle Eastern (MID) AF: 0.262 AC: 76 AN: 290

European-Non Finnish (NFE) AF: 0.174 AC: 11634 AN: 66824

Other (OTH) AF: 0.290 AC: 603 AN: 2080

Alfa AF: 0.276 Hom.: 988

Bravo AF: 0.352

Asia WGS AF: 0.397 AC: 1347 AN: 3408

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 01, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.14
PhyloP100		0.16
PromoterAI		-0.35	Neutral
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: rs3733873; hg19: chr5-176561113; COSMIC: COSV61780281; COSMIC: COSV61780281;