15-24955890-C-T

Variant names:

• chr15-24955890-C-T
• rs220028
• NM_003097.6:c.-391+828C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003097.6(SNRPN):​c.-391+828C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 151,112 control chromosomes in the GnomAD database, including 18,321 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.48 (18321 hom., cov: 28)
• Consequence: SNRPN NM_003097.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64
• Publications: 10 publications found

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]

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]

ENSG00000214265 (HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNRPN	NM_003097.6	c.-391+828C>T		intron_variant	Intron 1 of 9	ENST00000390687.9	NP_003088.1
SNURF	NM_001394334.1	c.14+828C>T		intron_variant	Intron 1 of 2	ENST00000577949.6	NP_001381263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNRPN	ENST00000390687.9	c.-391+828C>T		intron_variant	Intron 1 of 9	1	NM_003097.6	ENSP00000375105.4
SNURF	ENST00000577949.6	c.14+828C>T		intron_variant	Intron 1 of 2	2	NM_001394334.1	ENSP00000463201.1
ENSG00000214265	ENST00000551312.6	n.14+828C>T		intron_variant	Intron 1 of 7	5		ENSP00000451421.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 71882 AN: 150992 Hom.: 18275 Cov.: 28

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.466

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.476 AC: 71987 AN: 151112 Hom.: 18321 Cov.: 28 AF XY: 0.469 AC XY: 34554 AN XY: 73752

African (AFR) AF: 0.652 AC: 26848 AN: 41148

American (AMR) AF: 0.500 AC: 7592 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1477 AN: 3464

East Asian (EAS) AF: 0.508 AC: 2560 AN: 5036

South Asian (SAS) AF: 0.203 AC: 966 AN: 4760

European-Finnish (FIN) AF: 0.332 AC: 3485 AN: 10490

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27690 AN: 67734

Other (OTH) AF: 0.462 AC: 967 AN: 2094

Alfa AF: 0.444 Hom.: 7950

Bravo AF: 0.504

Asia WGS AF: 0.372 AC: 1291 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.4
DANN	Benign	0.56
PhyloP100		-1.6
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs220028; hg19: chr15-25201037; COSMIC: COSV57600115;