15-24679516-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018958.3(NPAP1):c.*178T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 618,436 control chromosomes in the GnomAD database, including 22,559 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 0.27 (5567 hom., cov: 33)
  • Exomes 𝑓: 0.27 (16992 hom.)
• Consequence: NPAP1 NM_018958.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0720

Genes affected

NPAP1 (HGNC:1190): (nuclear pore associated protein 1) This intronless retrogene is located in the Prader-Willi syndrome region on chromosome 15. This gene exhibits tissue-specific imprinting. Expression in adult testis and brain is biallelic, while expression in fetal brain is monoallelic and only from the paternal chromosome. The encoded protein is associated with the nuclear pore complex. [provided by RefSeq, Mar 2021]

PWRN1 (HGNC:33235): (Prader-Willi region non-protein coding RNA 1) This gene is located in the Prader-Willi syndrome (PWS) region of chromosome 15, which is known to undergo imprinting. The transcript is believed to be non-coding. It is bi-allelically expressed in testis and kidney, but mono-allelically expressed from the paternal allele in brain. This gene is poly-adenylated and is known to undergo alternative splicing. Transcript variants may represent part of a complex imprinting center-SNURF-SNRPN transcription unit. The contribution of this gene to the PWS phenotype is unknown, but it has been suggested that it may play a role in establishing paternal imprinting in the PWS region, perhaps by maintaining the paternal allele in an open chromatin configuration. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPAP1	NM_018958.3	c.*178T>C		3_prime_UTR_variant	1/1	ENST00000329468.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPAP1	ENST00000329468.5	c.*178T>C		3_prime_UTR_variant	1/1		NM_018958.3	P1
PWRN1	ENST00000652025.1	n.1487+55411T>C		intron_variant, non_coding_transcript_variant
PWRN1	ENST00000652139.1	n.605-52763T>C		intron_variant, non_coding_transcript_variant
PWRN1	ENST00000652735.1	n.892+55411T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40711 AN: 151988 Hom.: 5559 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.273

GnomAD4 exome AF: 0.269 AC: 125491 AN: 466328 Hom.: 16992 Cov.: 4 AF XY: 0.269 AC XY: 66103 AN XY: 245396

Gnomad4 AFR exome AF: 0.262

Gnomad4 AMR exome AF: 0.271

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.271

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.272

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.268 AC: 40747 AN: 152108 Hom.: 5567 Cov.: 33 AF XY: 0.269 AC XY: 19970 AN XY: 74332

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.253

Gnomad4 NFE AF: 0.268

Gnomad4 OTH AF: 0.273

Alfa AF: 0.272 Hom.: 6032

Bravo AF: 0.271

Asia WGS AF: 0.307 AC: 1067 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	3.2
Dann	Benign	0.62

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: rs12902137; hg19: chr15-24924663; COSMIC: COSV61507209;