rs1554189972

Variant names:

• chr5-177211433-C-CGTTCAGACTGTGTTACTAG
• rs1554189972
• NM_022455.5:c.3036_3054dupTTCAGACTGTGTTACTAGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_022455.5(NSD1):​c.3036_3054dupTTCAGACTGTGTTACTAGG​(p.Arg1019PhefsTer6) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 NM_022455.5 frameshift, stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.29
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-177211433-C-CGTTCAGACTGTGTTACTAG is Pathogenic according to our data. Variant chr5-177211433-C-CGTTCAGACTGTGTTACTAG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 547720.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3036_3054dupTTCAGACTGTGTTACTAGG	p.Arg1019PhefsTer6	frameshift stop_gained	Exon 5 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.3036_3054dupTTCAGACTGTGTTACTAGG	p.Arg1019PhefsTer6	frameshift stop_gained	Exon 5 of 23	NP_001396230.1
	NSD1	NM_001409302.1		c.3036_3054dupTTCAGACTGTGTTACTAGG	p.Arg1019PhefsTer6	frameshift stop_gained	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.3036_3054dupTTCAGACTGTGTTACTAGG	p.Arg1019PhefsTer6	frameshift stop_gained	Exon 5 of 23	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.2163_2181dupTTCAGACTGTGTTACTAGG	p.Arg728PhefsTer6	frameshift stop_gained	Exon 6 of 24	ENSP00000343209.5
	NSD1	ENST00000936190.1		c.3036_3054dupTTCAGACTGTGTTACTAGG	p.Arg1019PhefsTer6	frameshift stop_gained	Exon 5 of 23	ENSP00000606249.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Sotos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554189972; hg19: chr5-176638434;