chr15-25338938-T-C

Variant names:

• chr15-25338938-T-C
• rs182421497
• NM_130839.5:c.*199A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_130839.5(UBE3A):​c.*199A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00144 in 378,708 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: UBE3A NM_130839.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.15
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 15-25338938-T-C is Benign according to our data. Variant chr15-25338938-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1189552.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 260 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.*199A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.*199A>G		3_prime_UTR_variant	Exon 13 of 13		NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152110 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00126 AC: 286 AN: 226480 Hom.: 3 Cov.: 4 AF XY: 0.00101 AC XY: 118 AN XY: 117386

African (AFR) AF: 0.00 AC: 0 AN: 6032

American (AMR) AF: 0.00 AC: 0 AN: 8022

Ashkenazi Jewish (ASJ) AF: 0.000273 AC: 2 AN: 7322

East Asian (EAS) AF: 0.00 AC: 0 AN: 17120

South Asian (SAS) AF: 0.00 AC: 0 AN: 10858

European-Finnish (FIN) AF: 0.0181 AC: 207 AN: 11418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1066

European-Non Finnish (NFE) AF: 0.000419 AC: 63 AN: 150520

Other (OTH) AF: 0.000991 AC: 14 AN: 14122

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152228 Hom.: 3 Cov.: 32 AF XY: 0.00253 AC XY: 188 AN XY: 74440

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67982

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000476 Hom.: 0

Bravo AF: 0.000159

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 15, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.92
PhyloP100		6.2

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: rs182421497; hg19: chr15-25584085;