15-24974466-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.14

Variant links:

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]

SNRPN links:

ENSG00000214265 (HGNC:):

ENSG00000214265 links:

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]

SNURF links:

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]

SNHG14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SNRPN	NM_003097.6 link	c.3+10A>G		intron_variant	Intron 4 of 9	ENST00000390687.9	NP_003088.1	P63162-1X5DP00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNRPN	ENST00000390687.9 link	c.3+10A>G		intron_variant	Intron 4 of 9	1	NM_003097.6	ENSP00000375105.4		P63162-1
ENSG00000214265	ENST00000551312.6 link	n.*46-5070A>G		intron_variant	Intron 3 of 7	5		ENSP00000451421.1

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

846

AN:

152172

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00809

AC XY:

1087

AN XY:

134290

show subpopulations

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.:

Cov.:

AF XY:

0.00784

AC XY:

5701

AN XY:

726968

show subpopulations

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.:

Cov.:

AF XY:

0.00556

AC XY:

414

AN XY:

74484

show subpopulations

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.:

Bravo

AF:

0.00587

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autism spectrum disorder

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over