rs426541

Variant names:

• chr15-24962126-C-A
• rs426541
• NM_001394334.1:c.27C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-24962126-C-A
• chr15-24962126-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394334.1(SNURF):​c.27C>A​(p.His9Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNURF NM_001394334.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.546

Genes affected

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22846255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNURF	NM_001394334.1	c.27C>A	p.His9Gln	missense_variant	Exon 2 of 3	ENST00000577949.6	NP_001381263.1
SNRPN	NM_003097.6	c.-378C>A		5_prime_UTR_variant	Exon 2 of 10	ENST00000390687.9	NP_003088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNURF	ENST00000577949.6	c.27C>A	p.His9Gln	missense_variant	Exon 2 of 3	2	NM_001394334.1	ENSP00000463201.1
SNRPN	ENST00000390687	c.-378C>A		5_prime_UTR_variant	Exon 2 of 10	1	NM_003097.6	ENSP00000375105.4
ENSG00000214265	ENST00000551312.6	n.27C>A		non_coding_transcript_exon_variant	Exon 2 of 8	5		ENSP00000451421.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249016 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134806

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.9	.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	.;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.059	B;B
Vest4		0.55
MutPred		0.58		Loss of methylation at R12 (P = 0.0554);Loss of methylation at R12 (P = 0.0554);
MVP		0.40
ClinPred		0.51	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.054
gMVP		0.11

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: rs426541; hg19: chr15-25207273;