15-24974365-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003097.6(SNRPN):c.-89T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 1,221,690 control chromosomes in the GnomAD database, including 128,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22667 hom., cov: 32)
  • Exomes 𝑓: 0.44 (105528 hom.)
• Consequence: SNRPN NM_003097.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.651

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-24974365-T-C is Benign according to our data. Variant chr15-24974365-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 315447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNRPN	NM_003097.6	c.-89T>C		5_prime_UTR_variant	4/10	ENST00000390687.9
SNHG14	NR_146177.1	n.814T>C		non_coding_transcript_exon_variant	7/148

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNRPN	ENST00000390687.9	c.-89T>C		5_prime_UTR_variant	4/10	1	NM_003097.6	P1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79833 AN: 151978 Hom.: 22622 Cov.: 32

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.501

GnomAD4 exome AF: 0.436 AC: 466780 AN: 1069594 Hom.: 105528 Cov.: 14 AF XY: 0.429 AC XY: 236094 AN XY: 550940

Gnomad4 AFR exome AF: 0.755

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.418

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.435

Gnomad4 OTH exome AF: 0.455

GnomAD4 genome AF: 0.526 AC: 79933 AN: 152096 Hom.: 22667 Cov.: 32 AF XY: 0.518 AC XY: 38534 AN XY: 74344

Gnomad4 AFR AF: 0.752

Gnomad4 AMR AF: 0.522

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.526

Gnomad4 SAS AF: 0.275

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.496

Alfa AF: 0.448 Hom.: 32799

Bravo AF: 0.550

Asia WGS AF: 0.413 AC: 1436 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Autism spectrum disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.6
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs705; hg19: chr15-25219512;