ENST00000424333.6:n.5729-430C>T

Variant names:

• chr15-25278417-C-T
• rs142202250
• ENST00000424333.6:n.5729-430C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000424333.6(SNHG14):​n.5729-430C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 518,356 control chromosomes in the GnomAD database, including 6 homozygotes. 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: 𝑓 0.0053 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (4 hom.)
• Consequence: SNHG14 ENST00000424333.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.123
• Publications: 0 publications found

Genes affected

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]

SNORD109B (HGNC:32774): (small nucleolar RNA, C/D box 109B) This gene encodes a C/D box-type small nucleolar RNA that is expressed predominantly in the brain. Expression of this RNA is not detectable in the brains of patients with Prader-Willi syndrome. [provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNHG14	NR_146177.1	n.18355-430C>T		intron_variant	Intron 145 of 147
SNORD109B	NR_001289.1	n.*8C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNHG14	ENST00000424333.6	n.5729-430C>T		intron_variant	Intron 52 of 53	1
SNHG14	ENST00000554726.2	n.447-426C>T		intron_variant	Intron 5 of 6	1
SNHG14	ENST00000452731.5	n.841-430C>T		intron_variant	Intron 7 of 8	5

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152066 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.00483

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00329 AC: 753 AN: 228852 AF XY: 0.00287

Gnomad AFR exome AF: 0.00664

Gnomad AMR exome AF: 0.00837

Gnomad ASJ exome AF: 0.00531

Gnomad EAS exome AF: 0.00370

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00461

GnomAD4 exome AF: 0.00303 AC: 1109 AN: 366172 Hom.: 4 Cov.: 0 AF XY: 0.00278 AC XY: 584 AN XY: 209966

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00658 AC: 69 AN: 10490

American (AMR) AF: 0.00845 AC: 305 AN: 36076

Ashkenazi Jewish (ASJ) AF: 0.00607 AC: 71 AN: 11692

East Asian (EAS) AF: 0.00373 AC: 49 AN: 13154

South Asian (SAS) AF: 0.00335 AC: 223 AN: 66584

European-Finnish (FIN) AF: 0.00343 AC: 58 AN: 16904

Middle Eastern (MID) AF: 0.00210 AC: 6 AN: 2852

European-Non Finnish (NFE) AF: 0.00141 AC: 271 AN: 191810

Other (OTH) AF: 0.00343 AC: 57 AN: 16610

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00530 AC: 806 AN: 152184 Hom.: 2 Cov.: 32 AF XY: 0.00534 AC XY: 397 AN XY: 74404

African (AFR) AF: 0.0105 AC: 436 AN: 41546

American (AMR) AF: 0.00746 AC: 114 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00923 AC: 32 AN: 3468

East Asian (EAS) AF: 0.00504 AC: 26 AN: 5162

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00193 AC: 131 AN: 68000

Other (OTH) AF: 0.00617 AC: 13 AN: 2106

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.00602

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SNHG14: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	4.6
DANN	Benign	0.52
PhyloP100		-0.12

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs142202250; hg19: chr15-25523564;