chr15-25339101-CTTCCTTTTTTTTGT-C

Position:

• chr15-25339101-CTTCCTTTTTTTTGT-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_130839.5(UBE3A):​c.*22_*35del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,451,854 control chromosomes in the GnomAD database, including 61 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (56 hom.)
• Consequence: UBE3A NM_130839.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.790

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 -12 ACMG points.

• BP6: Variant 15-25339101-CTTCCTTTTTTTTGT-C is Benign according to our data. Variant chr15-25339101-CTTCCTTTTTTTTGT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1217730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 835 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBE3A	NM_130839.5	c.*22_*35del		3_prime_UTR_variant	13/13	ENST00000648336.2
SNHG14	NR_146177.1	n.18393-52492_18393-52479del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBE3A	ENST00000648336.2	c.*22_*35del		3_prime_UTR_variant	13/13		NM_130839.5	P1
SNHG14	ENST00000656420.1	n.5456+60220_5456+60233del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 835 AN: 151062 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00136

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00594

Gnomad ASJ AF: 0.0119

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00874

Gnomad OTH AF: 0.00626

GnomAD3 exomes AF: 0.00704 AC: 758 AN: 107646 Hom.: 4 AF XY: 0.00692 AC XY: 411 AN XY: 59382

Gnomad AFR exome AF: 0.00225

Gnomad AMR exome AF: 0.00783

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000184

Gnomad FIN exome AF: 0.00381

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00730

GnomAD4 exome AF: 0.00805 AC: 10466 AN: 1300678 Hom.: 56 AF XY: 0.00779 AC XY: 4969 AN XY: 637790

Gnomad4 AFR exome AF: 0.00151

Gnomad4 AMR exome AF: 0.00664

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000965

Gnomad4 FIN exome AF: 0.00293

Gnomad4 NFE exome AF: 0.00921

Gnomad4 OTH exome AF: 0.00702

GnomAD4 genome AF: 0.00552 AC: 835 AN: 151176 Hom.: 5 Cov.: 32 AF XY: 0.00505 AC XY: 373 AN XY: 73824

Gnomad4 AFR AF: 0.00136

Gnomad4 AMR AF: 0.00594

Gnomad4 ASJ AF: 0.0119

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00874

Gnomad4 OTH AF: 0.00620

Alfa AF: 0.00551 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SNHG14: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2019	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs573271880; hg19: chr15-25584248;