chr15-24676346-T-G

Position:

• chr15-24676346-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018958.3(NPAP1):​c.479T>G​(p.Val160Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,536,138 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (19 hom.)
• Consequence: NPAP1 NM_018958.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.226

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026224256).
• BP6: Variant 15-24676346-T-G is Benign according to our data. Variant chr15-24676346-T-G is described in ClinVar as [Benign]. Clinvar id is 768686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00765 (1157/151304) while in subpopulation AFR AF= 0.0264 (1085/41168). AF 95% confidence interval is 0.0251. There are 15 homozygotes in gnomad4. There are 579 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPAP1	NM_018958.3	c.479T>G	p.Val160Gly	missense_variant	1/1	ENST00000329468.5	NP_061831.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPAP1	ENST00000329468.5	c.479T>G	p.Val160Gly	missense_variant	1/1	6	NM_018958.3	ENSP00000333735.3

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1156 AN: 151192 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00771

GnomAD3 exomes AF: 0.00254 AC: 468 AN: 184524 Hom.: 8 AF XY: 0.00177 AC XY: 172 AN XY: 97224

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.000901

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000568

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.000806 AC: 1116 AN: 1384834 Hom.: 19 Cov.: 33 AF XY: 0.000685 AC XY: 467 AN XY: 681428

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000371

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00765 AC: 1157 AN: 151304 Hom.: 15 Cov.: 33 AF XY: 0.00784 AC XY: 579 AN XY: 73854

Gnomad4 AFR AF: 0.0264

Gnomad4 AMR AF: 0.00335

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.00763

Alfa AF: 0.000792 Hom.: 0

Bravo AF: 0.00863

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00243 AC: 292

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.49
DANN	Benign	0.21
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.022
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.030	D
Polyphen		0.034	B
Vest4		0.099
MVP		0.030
MPC		0.095
ClinPred		0.014	T
GERP RS		-4.3
Varity_R		0.054
gMVP		0.093

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: rs34391654; hg19: chr15-24921493;