rs189499374

Variant names:

• chr15-24675947-C-A
• rs189499374
• NM_018958.3:c.80C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-24675947-C-A
• chr15-24675947-C-G
• chr15-24675947-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018958.3(NPAP1):​c.80C>A​(p.Pro27His) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPAP1 NM_018958.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 0 publications found

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]

ENSG00000286110 (HGNC:):

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066994846).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018958.3. 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
	NPAP1	NM_018958.3	MANE Select	c.80C>A	p.Pro27His	missense	Exon 1 of 1	NP_061831.2	Q9NZP6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPAP1	ENST00000329468.5	TSL:6 MANE Select	c.80C>A	p.Pro27His	missense	Exon 1 of 1	ENSP00000333735.3	Q9NZP6
	ENSG00000286110	ENST00000650707.1		n.407+105819C>A		intron	N/A
	ENSG00000286110	ENST00000651136.1		n.1530+51842C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.2
DANN	Benign	0.86
DEOGEN2	Benign	0.0047	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.00075	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.53
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.026
Sift	Benign	0.056	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.090	B
Vest4		0.14
MutPred		0.21		Loss of loop (P = 0.0603)
MVP		0.030
MPC		0.40
ClinPred		0.13	T
GERP RS		-4.8
PromoterAI		-0.18	Neutral
Varity_R		0.057
gMVP		0.28

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: rs189499374; hg19: chr15-24921094;