15-24829900-A-G

Position:

• chr15-24829900-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001378251.1(SNRPN):​c.-817A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 152,282 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: SNRPN NM_001378251.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.269

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]

ENSG00000286110 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00214 (326/152182) while in subpopulation EAS AF= 0.0234 (121/5166). AF 95% confidence interval is 0.02. There are 2 homozygotes in gnomad4. There are 220 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 326 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNRPN	NM_001378251.1	c.-817A>G		5_prime_UTR_variant	2/14		NP_001365180.1
SNRPN	NM_001349457.2	c.-752A>G		5_prime_UTR_variant	2/14		NP_001336386.1
SNRPN	NM_001349458.2	c.-584A>G		5_prime_UTR_variant	2/13		NP_001336387.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNRPN	ENST00000400100	c.-584A>G		5_prime_UTR_variant	2/13	1		ENSP00000382972.1
SNRPN	ENST00000642807	c.-772A>G		5_prime_UTR_variant	2/14			ENSP00000495345.1
SNRPN	ENST00000645002	c.-883A>G		5_prime_UTR_variant	2/15			ENSP00000494831.1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152064 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0236

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.0100 AC: 1 AN: 100 Hom.: 0 Cov.: 0 AF XY: 0.0179 AC XY: 1 AN XY: 56

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0208

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152182 Hom.: 2 Cov.: 32 AF XY: 0.00296 AC XY: 220 AN XY: 74412

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0234

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000684 Hom.: 0

Bravo AF: 0.00169

Asia WGS AF: 0.0160 AC: 54 AN: 3478

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	-1.0
CADD	Benign	4.7
DANN	Benign	0.48

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: rs58890023; hg19: chr15-25075047;