Genetic Variant NPL:p.Val85Ile (chr1-182812178-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_030769.3(NPL):c.253G>A(p.Val85Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000652 in 1,613,956 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00097 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 4 hom. )

Consequence

NPL
NM_030769.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.04

Variant links:

Genes affected

NPL (HGNC:16781): (N-acetylneuraminate pyruvate lyase) This gene encodes a member of the N-acetylneuraminate lyase sub-family of (beta/alpha)(8)-barrel enzymes. N-acetylneuraminate lyases regulate cellular concentrations of N-acetyl-neuraminic acid (sialic acid) by mediating the reversible conversion of sialic acid into N-acetylmannosamine and pyruvate. A pseudogene of this gene is located on the short arm of chromosome 2. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jan 2011]

NPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057174563).

BP6

Variant 1-182812178-G-A is Benign according to our data. Variant chr1-182812178-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2639619.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPL	NM_030769.3 link	c.253G>A	p.Val85Ile	missense_variant	Exon 6 of 13	ENST00000367553.6	NP_110396.1	Q9BXD5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPL	ENST00000367553.6 link	c.253G>A	p.Val85Ile	missense_variant	Exon 6 of 13	1	NM_030769.3	ENSP00000356524.1		Q9BXD5-1

Frequencies

GnomAD3 genomes

AF:

0.000973

AC:

148

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000577

AC:

145

AN:

251230

Hom.:

AF XY:

0.000545

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00234

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000819

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000618

AC:

904

AN:

1461678

Hom.:

Cov.:

AF XY:

0.000639

AC XY:

465

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00182

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000693

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000972

AC:

148

AN:

152278

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000663

Hom.:

Bravo

AF:

0.00103

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000675

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000948

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPL: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;.;D;.;D;T

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;.;.;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.057

T;T;T;T;T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.5

.;M;M;M;M;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.0

N;N;N;N;N;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0090

D;D;D;D;D;.

Sift4G

Uncertain

0.015

D;D;D;D;D;T

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.59

MVP

0.83

MPC

0.53

ClinPred

0.042

GERP RS

5.2

Varity_R

0.56

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over