NM_022455.5:c.2047_2048delAA

Variant names:

• chr5-177210443-GAA-G
• rs587784079
• NM_022455.5:c.2047_2048delAA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_022455.5(NSD1):​c.2047_2048delAA​(p.Lys683AspfsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 NM_022455.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.98
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-177210443-GAA-G is Pathogenic according to our data. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-177210443-GAA-G is described in CliVar as Pathogenic. Clinvar id is 817335.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSD1	NM_022455.5	c.2047_2048delAA	p.Lys683AspfsTer5	frameshift_variant	Exon 5 of 23	ENST00000439151.7	NP_071900.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSD1	ENST00000439151.7	c.2047_2048delAA	p.Lys683AspfsTer5	frameshift_variant	Exon 5 of 23	1	NM_022455.5	ENSP00000395929.2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 06, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2047_2048delAA pathogenic variant in the NSD1 gene causes a frameshift starting with codon Lysine 683, changes this amino acid to an Aspartate residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Lys683AspfsX5. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2047_2048delAA variant is not observed in large population cohorts (Lek et al., 2016). Although this pathogenic variant has not been previously reported to our knowledge, its presence is consistent with the diagnosis of Sotos syndrome in this individual. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs587784079; hg19: chr5-176637444;