rs587784182

Variant names:

• chr5-177288805-G-A
• rs587784182
• NM_022455.5:c.6152-14G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-177288805-G-A
• chr5-177288805-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3 PP5

The NM_022455.5(NSD1):​c.6152-14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005461999: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSD1 NM_022455.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6
• Conservation: PhyloP100: -0.295
• 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: 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005461999: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-177288805-G-A is Pathogenic according to our data. Variant chr5-177288805-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159403.

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.6152-14G>A		intron	N/A	NP_071900.2
	NSD1	NM_001409301.1		c.6152-14G>A		intron	N/A	NP_001396230.1	Q96L73-1
	NSD1	NM_001409302.1		c.6152-14G>A		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.6152-14G>A		intron	N/A	ENSP00000395929.2	Q96L73-1
	NSD1	ENST00000347982.9	TSL:1	c.5279-14G>A		intron	N/A	ENSP00000343209.5	A0A8I5QJP2
	NSD1	ENST00000936190.1		c.6152-14G>A		intron	N/A	ENSP00000606249.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	4	-	not provided (5)
-	2	-	Sotos syndrome (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.7
DANN	Benign	0.70
PhyloP100		-0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 2
DS_AL_spliceai		0.71		Position offset: 14

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

Other links and lift over

dbSNP: rs587784182; hg19: chr5-176715806;