rs10519485

Positions:

• chr15-25356954-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_130839.5(UBE3A):​c.1754-58T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,359,076 control chromosomes in the GnomAD database, including 462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (41 hom., cov: 32)
  • Exomes 𝑓: 0.022 (421 hom.)
• Consequence: UBE3A NM_130839.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-25356954-A-C is Benign according to our data. Variant chr15-25356954-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0175 (2672/152334) while in subpopulation NFE AF= 0.025 (1701/68028). AF 95% confidence interval is 0.024. There are 41 homozygotes in gnomad4. There are 1266 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2672 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBE3A	NM_130839.5	c.1754-58T>G		intron_variant		ENST00000648336.2	NP_570854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBE3A	ENST00000648336.2	c.1754-58T>G		intron_variant			NM_130839.5	ENSP00000497572.2

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2674 AN: 152216 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.0858

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00602

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0250

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.0220 AC: 26569 AN: 1206742 Hom.: 421 AF XY: 0.0218 AC XY: 13327 AN XY: 611042

Gnomad4 AFR exome AF: 0.00387

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0875

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00303

Gnomad4 FIN exome AF: 0.00785

Gnomad4 NFE exome AF: 0.0240

Gnomad4 OTH exome AF: 0.0265

GnomAD4 genome AF: 0.0175 AC: 2672 AN: 152334 Hom.: 41 Cov.: 32 AF XY: 0.0170 AC XY: 1266 AN XY: 74496

Gnomad4 AFR AF: 0.00457

Gnomad4 AMR AF: 0.0230

Gnomad4 ASJ AF: 0.0858

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00602

Gnomad4 NFE AF: 0.0250

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0214 Hom.: 5

Bravo AF: 0.0185

Asia WGS AF: 0.00232 AC: 8 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.6
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs10519485; hg19: chr15-25602101;