15-24974365-T-C

Variant names:

• chr15-24974365-T-C
• rs705
• NM_003097.6:c.-89T>C

Variant summary

Our verdict is Benign. The variant received -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:3 O:1
• Conservation: PhyloP100: -0.651
• Publications: 31 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:):

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]

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
SNRPN	NM_003097.6	c.-89T>C		5_prime_UTR_variant	Exon 4 of 10	ENST00000390687.9	NP_003088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNRPN	ENST00000390687.9	c.-89T>C		5_prime_UTR_variant	Exon 4 of 10	1	NM_003097.6	ENSP00000375105.4
ENSG00000214265	ENST00000551312.6	n.*46-5171T>C		intron_variant	Intron 3 of 7	5		ENSP00000451421.1

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

African (AFR) AF: 0.755 AC: 19379 AN: 25672

American (AMR) AF: 0.523 AC: 23058 AN: 44074

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 9846 AN: 23576

East Asian (EAS) AF: 0.500 AC: 18936 AN: 37894

South Asian (SAS) AF: 0.279 AC: 21850 AN: 78178

European-Finnish (FIN) AF: 0.406 AC: 21549 AN: 53140

Middle Eastern (MID) AF: 0.423 AC: 2129 AN: 5030

European-Non Finnish (NFE) AF: 0.435 AC: 328498 AN: 754658

Other (OTH) AF: 0.455 AC: 21535 AN: 47372

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

African (AFR) AF: 0.752 AC: 31186 AN: 41490

American (AMR) AF: 0.522 AC: 7961 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1494 AN: 3470

East Asian (EAS) AF: 0.526 AC: 2716 AN: 5160

South Asian (SAS) AF: 0.275 AC: 1330 AN: 4828

European-Finnish (FIN) AF: 0.382 AC: 4041 AN: 10572

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29683 AN: 67990

Other (OTH) AF: 0.496 AC: 1050 AN: 2116

Alfa AF: 0.468 Hom.: 58339

Bravo AF: 0.550

Asia WGS AF: 0.413 AC: 1436 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autism spectrum disorder Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thalidomide response Other:1

Rare Diseases Genetics and Genomics, Islamia College Peshawar

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

this variant was associated with excellent response to thalidomide (achieving transfusion independence) excellent responsive

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-0.65
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs705; hg19: chr15-25219512;