chr15-24962126-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001394334.1(SNURF):​c.27C>T​(p.His9His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,614,098 control chromosomes in the GnomAD database, including 48 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 0.0095 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (29 hom.)
• Consequence: SNURF NM_001394334.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 15-24962126-C-T is Benign according to our data. Variant chr15-24962126-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 315440.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.546 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00952 (1449/152278) while in subpopulation AFR AF= 0.0322 (1338/41552). AF 95% confidence interval is 0.0308. There are 19 homozygotes in gnomad4. There are 648 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNURF	NM_001394334.1	c.27C>T	p.His9His	synonymous_variant	Exon 2 of 3	ENST00000577949.6	NP_001381263.1
SNRPN	NM_003097.6	c.-378C>T		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>T	p.His9His	synonymous_variant	Exon 2 of 3	2	NM_001394334.1	ENSP00000463201.1
SNRPN	ENST00000390687	c.-378C>T		5_prime_UTR_variant	Exon 2 of 10	1	NM_003097.6	ENSP00000375105.4
ENSG00000214265	ENST00000551312.6	n.27C>T		non_coding_transcript_exon_variant	Exon 2 of 8	5		ENSP00000451421.1

Frequencies

GnomAD3 genomes AF: 0.00950 AC: 1445 AN: 152160 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00320 AC: 798 AN: 249016 Hom.: 16 AF XY: 0.00234 AC XY: 316 AN XY: 134806

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000503

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00143 AC: 2087 AN: 1461820 Hom.: 29 Cov.: 31 AF XY: 0.00126 AC XY: 914 AN XY: 727216

Gnomad4 AFR exome AF: 0.0354

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00872

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000300

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.00952 AC: 1449 AN: 152278 Hom.: 19 Cov.: 32 AF XY: 0.00870 AC XY: 648 AN XY: 74442

Gnomad4 AFR AF: 0.0322

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00530 Hom.: 10

Bravo AF: 0.0113

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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	-0.42
CADD	Benign	7.7
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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;