15-24962118-C-T

Variant names:

• chr15-24962118-C-T
• rs776280755
• NM_003097.6:c.-386C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003097.6(SNRPN):​c.-386C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SNRPN NM_003097.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11
• 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]

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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21776396).
• BS2: High AC in GnomAdExome4 at 17 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.-386C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	NP_003088.1	X5DP00
	SNURF	NM_001394334.1	MANE Select	c.19C>T	p.Arg7Cys	missense	Exon 2 of 3	NP_001381263.1	Q9Y675
	SNRPN	NM_003097.6	MANE Select	c.-386C>T		5_prime_UTR	Exon 2 of 10	NP_003088.1	X5DP00

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNRPN	ENST00000390687.9	TSL:1 MANE Select	c.-386C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	ENSP00000375105.4	P63162-1
	SNRPN	ENST00000400097.5	TSL:1	c.-386C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	ENSP00000382969.1	P63162-1
	SNRPN	ENST00000400100.5	TSL:1	c.-386C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 13	ENSP00000382972.1	P63162-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249012 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727156

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111828

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autism spectrum disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.92	T
PhyloP100		1.1
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.17
Sift	Benign	0.098	T
Sift4G	Uncertain	0.049	D
Polyphen		0.024	B
Vest4		0.58
MutPred		0.60		Loss of MoRF binding (P = 0.0208)
MVP		0.093
ClinPred		0.30	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.032
Mutation Taster		=99/1	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: rs776280755; hg19: chr15-25207265; COSMIC: COSV57599420;