NM_130839.5:c.1754-58T>G

Variant names:

• chr15-25356954-A-C
• rs10519485
• NM_130839.5:c.1754-58T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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 ClinVar as (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
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 2672 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130839.5. 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
	UBE3A	NM_130839.5	MANE Select	c.1754-58T>G		intron	N/A	NP_570854.1
	UBE3A	NM_000462.5		c.1763-58T>G		intron	N/A	NP_000453.2
	UBE3A	NM_001354505.1		c.1754-58T>G		intron	N/A	NP_001341434.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBE3A	ENST00000648336.2	MANE Select	c.1754-58T>G		intron	N/A	ENSP00000497572.2
	UBE3A	ENST00000566215.5	TSL:1	c.1694-58T>G		intron	N/A	ENSP00000457771.1
	SNHG14	ENST00000424333.6	TSL:1	n.5767-61834A>C		intron	N/A

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

African (AFR) AF: 0.00387 AC: 103 AN: 26630

American (AMR) AF: 0.0193 AC: 811 AN: 41956

Ashkenazi Jewish (ASJ) AF: 0.0875 AC: 2118 AN: 24192

East Asian (EAS) AF: 0.00 AC: 0 AN: 36348

South Asian (SAS) AF: 0.00303 AC: 233 AN: 76778

European-Finnish (FIN) AF: 0.00785 AC: 401 AN: 51078

Middle Eastern (MID) AF: 0.0207 AC: 85 AN: 4100

European-Non Finnish (NFE) AF: 0.0240 AC: 21456 AN: 894182

Other (OTH) AF: 0.0265 AC: 1362 AN: 51478

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

African (AFR) AF: 0.00457 AC: 190 AN: 41588

American (AMR) AF: 0.0230 AC: 352 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0858 AC: 298 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00602 AC: 64 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0250 AC: 1701 AN: 68028

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.6
DANN	Benign	0.73
PhyloP100		1.3
PromoterAI		-0.0033	Neutral
Mutation Taster		=100/0	polymorphism

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: rs10519485; hg19: chr15-25602101;