NM_018958.3:c.244C>G

Variant names:

• chr15-24676111-C-G
• rs199643130
• NM_018958.3:c.244C>G

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.244C>G​(p.Leu82Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,412,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPAP1 NM_018958.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.73
• 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=0.048716635).

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.244C>G	p.Leu82Val	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.244C>G	p.Leu82Val	missense	Exon 1 of 1	ENSP00000333735.3	Q9NZP6
	ENSG00000286110	ENST00000650707.1		n.407+105983C>G		intron	N/A
	ENSG00000286110	ENST00000651136.1		n.1530+52006C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1412628 Hom.: 0 Cov.: 32 AF XY: 0.00000286 AC XY: 2 AN XY: 699198

African (AFR) AF: 0.00 AC: 0 AN: 31616

American (AMR) AF: 0.00 AC: 0 AN: 37652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22428

East Asian (EAS) AF: 0.00 AC: 0 AN: 38692

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090464

Other (OTH) AF: 0.00 AC: 0 AN: 58232

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.2
DANN	Benign	0.96
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.00087	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.7
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.013
Sift	Benign	0.23	T
Sift4G	Benign	0.23	T
Polyphen		0.17	B
Vest4		0.022
MutPred		0.22		Gain of sheet (P = 0.0477)
MVP		0.030
MPC		0.22
ClinPred		0.099	T
GERP RS		-4.5
PromoterAI		-0.0034	Neutral
Varity_R		0.048
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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: rs199643130; hg19: chr15-24921258;