chr15-24974466-A-G

Variant names:

• chr15-24974466-A-G
• rs112560608
• NM_003097.6:c.3+10A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003097.6(SNRPN):​c.3+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00742 in 1,613,552 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0055 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (70 hom.)
• Consequence: SNRPN NM_003097.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.14
• Publications: 1 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]

ENSG00000214265 (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]

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-24974466-A-G is Benign according to our data. Variant chr15-24974466-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 315451.
• BS2: High AC in GnomAd4 at 845 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003097.6. 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_003097.6	MANE Select	c.3+10A>G		intron	N/A	NP_003088.1	X5DP00
	SNRPN	NM_001378251.1		c.-301-176A>G		intron	N/A	NP_001365180.1	P63162-2
	SNRPN	NM_001378252.1		c.-302+10A>G		intron	N/A	NP_001365181.1	P63162-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRPN	ENST00000390687.9	TSL:1 MANE Select	c.3+10A>G		intron	N/A	ENSP00000375105.4	P63162-1
	SNRPN	ENST00000400097.5	TSL:1	c.3+10A>G		intron	N/A	ENSP00000382969.1	P63162-1
	SNRPN	ENST00000400100.5	TSL:1	c.3+10A>G		intron	N/A	ENSP00000382972.1	P63162-1

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152172 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00736 AC: 1818 AN: 247112 AF XY: 0.00809

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.0257

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00794

Gnomad OTH exome AF: 0.00893

GnomAD4 exome AF: 0.00762 AC: 11132 AN: 1461262 Hom.: 70 Cov.: 30 AF XY: 0.00784 AC XY: 5701 AN XY: 726968

African (AFR) AF: 0.000897 AC: 30 AN: 33448

American (AMR) AF: 0.00382 AC: 171 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 672 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0150 AC: 1292 AN: 86238

European-Finnish (FIN) AF: 0.000730 AC: 39 AN: 53416

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5764

European-Non Finnish (NFE) AF: 0.00750 AC: 8335 AN: 1111474

Other (OTH) AF: 0.00866 AC: 523 AN: 60372

GnomAD4 genome AF: 0.00555 AC: 845 AN: 152290 Hom.: 11 Cov.: 32 AF XY: 0.00556 AC XY: 414 AN XY: 74484

African (AFR) AF: 0.00140 AC: 58 AN: 41560

American (AMR) AF: 0.00562 AC: 86 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 89 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4820

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00772 AC: 525 AN: 68018

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00703 Hom.: 2

Bravo AF: 0.00587

Asia WGS AF: 0.00577 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autism spectrum disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.018
DANN	Benign	0.77
PhyloP100		-1.1
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: rs112560608; hg19: chr15-25219613;