15-24954984-G-A

Variant names:

• chr15-24954984-G-A
• rs186748238
• ENST00000400097.5:c.-390-7130G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001378251.1(SNRPN):​c.-548-7130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,607,612 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0052 (24 hom.)
• Consequence: SNRPN NM_001378251.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.23
• Publications: 2 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]

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]

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:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-24954984-G-A is Benign according to our data. Variant chr15-24954984-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3387943.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 472 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378251.1. 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
	SNRPN	NM_001378251.1		c.-548-7130G>A		intron	N/A	NP_001365180.1	P63162-2
	SNRPN	NM_001349454.2		c.-370-3754G>A		intron	N/A	NP_001336383.1	P63162-1
	SNRPN	NM_001349455.2		c.-390-7130G>A		intron	N/A	NP_001336384.1	X5DP00

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRPN	ENST00000400097.5	TSL:1	c.-390-7130G>A		intron	N/A	ENSP00000382969.1	P63162-1
	SNRPN	ENST00000400100.5	TSL:1	c.-390-7130G>A		intron	N/A	ENSP00000382972.1	P63162-1
	SNRPN	ENST00000554227.6	TSL:5	c.-897G>A		5_prime_UTR	Exon 1 of 12	ENSP00000452342.2	P63162-2

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 472 AN: 152246 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00536

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00519 AC: 7548 AN: 1455248 Hom.: 24 Cov.: 30 AF XY: 0.00490 AC XY: 3546 AN XY: 723700

African (AFR) AF: 0.00108 AC: 36 AN: 33370

American (AMR) AF: 0.00138 AC: 61 AN: 44114

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25936

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.000446 AC: 38 AN: 85266

European-Finnish (FIN) AF: 0.00142 AC: 75 AN: 52902

Middle Eastern (MID) AF: 0.000699 AC: 3 AN: 4292

European-Non Finnish (NFE) AF: 0.00639 AC: 7096 AN: 1109826

Other (OTH) AF: 0.00397 AC: 238 AN: 59962

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152364 Hom.: 2 Cov.: 31 AF XY: 0.00286 AC XY: 213 AN XY: 74508

African (AFR) AF: 0.00118 AC: 49 AN: 41594

American (AMR) AF: 0.00196 AC: 30 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00537 AC: 365 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00458 Hom.: 1

Bravo AF: 0.00323

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.063
DANN	Benign	0.91
PhyloP100		-4.2
PromoterAI		0.017	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: rs186748238; hg19: chr15-25200131;