rs587784211

Variant names:

• chr5-177293995-GCCCAATCCTCTGGAA-G
• rs587784211
• NM_022455.5:c.6630_6644delCAATCCTCTGGAACC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM4 PP3 PP5_Moderate

The ENST00000439151.7(NSD1):​c.6630_6644delCAATCCTCTGGAACC​(p.Asn2211_Pro2215del) variant causes a disruptive inframe deletion change involving the alteration of a 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 DEL_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 (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: NSD1 ENST00000439151.7 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.95
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000439151.7
• PM4: Nonframeshift variant in NON repetitive region in ENST00000439151.7.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 5-177293995-GCCCAATCCTCTGGAA-G is Pathogenic according to our data. Variant chr5-177293995-GCCCAATCCTCTGGAA-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 159433.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000439151.7. 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.6630_6644delCAATCCTCTGGAACC	p.Asn2211_Pro2215del	disruptive_inframe_deletion	Exon 23 of 23	NP_071900.2
	NSD1	NM_001409301.1		c.6630_6644delCAATCCTCTGGAACC	p.Asn2211_Pro2215del	disruptive_inframe_deletion	Exon 23 of 23	NP_001396230.1
	NSD1	NM_001409302.1		c.6630_6644delCAATCCTCTGGAACC	p.Asn2211_Pro2215del	disruptive_inframe_deletion	Exon 23 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.6630_6644delCAATCCTCTGGAACC	p.Asn2211_Pro2215del	disruptive_inframe_deletion	Exon 23 of 23	ENSP00000395929.2
	NSD1	ENST00000347982.9	TSL:1	c.5757_5771delCAATCCTCTGGAACC	p.Asn1920_Pro1924del	disruptive_inframe_deletion	Exon 24 of 24	ENSP00000343209.5
	NSD1	ENST00000687453.1		c.6321_6335delCAATCCTCTGGAACC	p.Asn2108_Pro2112del	disruptive_inframe_deletion	Exon 20 of 20	ENSP00000508426.1

Frequencies

GnomAD3 genomes Cov.: 30

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

GnomAD4 genome Cov.: 30

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		8.9
Mutation Taster		=15/185	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587784211; hg19: chr5-176720996;