rs587780585

Variant names:

• chr15-25370734-TATAAAGGGACATGTC-T
• rs587780585
• NM_130839.5:c.1425_1439delGACATGTCCCTTTAT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP3 PP5

The NM_130839.5(UBE3A):​c.1425_1439delGACATGTCCCTTTAT​(p.Met475_Phe479del) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UBE3A NM_130839.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

UBE3A (HGNC:12496): (ubiquitin protein ligase E3A) This gene encodes an E3 ubiquitin-protein ligase, part of the ubiquitin protein degradation system. This imprinted gene is maternally expressed in brain and biallelically expressed in other tissues. Maternally inherited deletion of this gene causes Angelman Syndrome, characterized by severe motor and intellectual retardation, ataxia, hypotonia, epilepsy, absence of speech, and characteristic facies. The protein also interacts with the E6 protein of human papillomavirus types 16 and 18, resulting in ubiquitination and proteolysis of tumor protein p53. Alternative splicing of this gene results in three transcript variants encoding three isoforms with different N-termini. Additional transcript variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

SNHG14 (HGNC:37462): (small nucleolar RNA host gene 14) This gene is located within the Prader-Willi critical region and produces a long, spliced paternally-imprinted RNA that initiates within a common upstream promoter region shared by the SNRPN (small nuclear ribonucleoprotein polypeptide N) and SNURF genes. This transcript serves as a host RNA for the small nucleolar RNA, C/D box 115 and 116 clusters. This RNA extends in antisense into the region of the ubiquitin protein ligase E3A gene (UBE3A), and is thought to regulate imprinted expression of UBE3A in the brain. This transcript undergoes extensive alternative splicing, and may initiate and terminate at multiple locations within this genomic region. The full-length structure of all splice forms is not determined. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a region_of_interest Interaction with HCV core protein (size 99) in uniprot entity UBE3A_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_130839.5
• PM4: Nonframeshift variant in NON repetitive region in NM_130839.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 15-25370734-TATAAAGGGACATGTC-T is Pathogenic according to our data. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-25370734-TATAAAGGGACATGTC-T is described in CliVar as Pathogenic. Clinvar id is 136208.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.1425_1439delGACATGTCCCTTTAT	p.Met475_Phe479del	disruptive_inframe_deletion	Exon 6 of 13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.1425_1439delGACATGTCCCTTTAT	p.Met475_Phe479del	disruptive_inframe_deletion	Exon 6 of 13		NM_130839.5	ENSP00000497572.2

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: no assertion criteria provided

Submissions by phenotype

Angelman syndrome Pathogenic:1

Feb 14, 2014

Baylor Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587780585; hg19: chr15-25615881;