15-24974368-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003097.6(SNRPN):c.-86G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000772 in 1,283,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: SNRPN NM_003097.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.27

Genes affected

SNRPN (HGNC:11164): (small nuclear ribonucleoprotein polypeptide N) This gene is located within the Prader-Willi Syndrome critical region on chromosome 15 and is imprinted and expressed from the paternal allele. It encodes a component of the small nuclear ribonucleoprotein complex, which functions in pre-mRNA processing and may contribute to tissue-specific alternative splicing. Alternative promoter use and alternative splicing result in a multitude of transcript variants encoding the same protein. Transcript variants that initiate at the CpG island-associated imprinting center may be bicistronic and also encode the SNRPN upstream reading frame protein (SNURF) from an upstream open reading frame. In addition, long spliced transcripts for small nucleolar RNA host gene 14 (SNHG14) may originate from the promoters at this locus and share exons with this gene. Alterations in this region are associated with parental imprint switch failure, which may cause Angelman syndrome or Prader-Willi syndrome. [provided by RefSeq, Mar 2017]

SNHG14 (HGNC:):

SNURF (HGNC:11171): (SNRPN upstream open reading frame) This gene is located within the Prader-Willi Syndrome critical region on chromosome 15. Transcripts produced from this gene initiate at an imprinting center and are paternally-imprinted. These transcripts may be bicistronic and also encode SNRPN (small nuclear ribonucleoprotein polypeptide N) from a downstream open reading frame. The small protein represented by this gene is encoded by an evolutionarily-conserved upstream open reading frame and is localized to the nucleus. Extensive alternative splicing and promoter usage occurs in this region and the full-length nature of some of these transcripts has not been determined. Alterations in the imprinting center are associated with parental imprint switch failure, which may cause Angelman syndrome or Prader-Willi syndrome. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNRPN	NM_003097.6	c.-86G>A		5_prime_UTR_variant	4/10	ENST00000390687.9
SNHG14	NR_146177.1	n.817G>A		non_coding_transcript_exon_variant	7/148

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNRPN	ENST00000390687.9	c.-86G>A		5_prime_UTR_variant	4/10	1	NM_003097.6	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000734 AC: 83 AN: 1130810 Hom.: 0 Cov.: 16 AF XY: 0.0000725 AC XY: 42 AN XY: 579084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.0000785

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000197

Gnomad4 OTH exome AF: 0.000142

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74442

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000110

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autism spectrum disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.97
Dann	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs886051018; hg19: chr15-25219515; COSMIC: COSV100578763; COSMIC: COSV100578763;