chr15-24974466-A-G

Position:

• chr15-24974466-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 315451.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr15-24974466-A-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 845 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNRPN	NM_003097.6	c.3+10A>G		intron_variant		ENST00000390687.9	NP_003088.1
SNHG14	NR_146177.1	n.905+10A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNRPN	ENST00000390687.9	c.3+10A>G		intron_variant		1	NM_003097.6	ENSP00000375105	P1

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

GnomAD3 exomes AF: 0.00736 AC: 1818 AN: 247112 Hom.: 19 AF XY: 0.00809 AC XY: 1087 AN XY: 134290

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 SAS exome AF: 0.0157

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

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.00382

Gnomad4 ASJ exome AF: 0.0257

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.000730

Gnomad4 NFE exome AF: 0.00750

Gnomad4 OTH exome AF: 0.00866

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

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00772

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00703 Hom.: 2

Bravo AF: 0.00587

Asia WGS AF: 0.00577 AC: 21 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autism spectrum disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.018
DANN	Benign	0.77

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: rs112560608; hg19: chr15-25219613;