rs35214605

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004813.4(PEX16):c.760G>C(p.Val254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,600,486 control chromosomes in the GnomAD database, including 456 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 19 hom., cov: 33)

Exomes 𝑓: 0.022 ( 437 hom. )

Consequence

PEX16
NM_004813.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.702

Variant links:

Genes affected

PEX16 (HGNC:8857): (peroxisomal biogenesis factor 16) The protein encoded by this gene is an integral peroxisomal membrane protein. An inactivating nonsense mutation localized to this gene was observed in a patient with Zellweger syndrome of the complementation group CGD/CG9. Expression of this gene product morphologically and biochemically restores the formation of new peroxisomes, suggesting a role in peroxisome organization and biogenesis. Alternative splicing has been observed for this gene and two variants have been described. [provided by RefSeq, Jul 2008]

PEX16 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036569238).

BP6

Variant 11-45914138-C-G is Benign according to our data. Variant chr11-45914138-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 304788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-45914138-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0178 (2707/151976) while in subpopulation NFE AF= 0.0254 (1723/67946). AF 95% confidence interval is 0.0244. There are 19 homozygotes in gnomad4. There are 1301 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX16	NM_004813.4 linkuse as main transcript	c.760G>C	p.Val254Leu	missense_variant	8/11	ENST00000378750.10	NP_004804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX16	ENST00000378750.10 linkuse as main transcript	c.760G>C	p.Val254Leu	missense_variant	8/11	1	NM_004813.4	ENSP00000368024	P1	Q9Y5Y5-1

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2708

AN:

151856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00426

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0456

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0158

Gnomad FIN

AF:

0.0184

Gnomad MID

AF:

0.0417

Gnomad NFE

AF:

0.0254

Gnomad OTH

AF:

0.0216

GnomAD3 exomes

AF:

0.0194

AC:

4353

AN:

224696

Hom.:

AF XY:

0.0208

AC XY:

2535

AN XY:

122030

show subpopulations

Gnomad AFR exome

AF:

0.00368

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.0389

Gnomad EAS exome

AF:

0.000240

Gnomad SAS exome

AF:

0.0160

Gnomad FIN exome

AF:

0.0190

Gnomad NFE exome

AF:

0.0267

Gnomad OTH exome

AF:

0.0223

GnomAD4 exome

AF:

0.0221

AC:

32048

AN:

1448510

Hom.:

437

Cov.:

AF XY:

0.0224

AC XY:

16153

AN XY:

719650

show subpopulations

Gnomad4 AFR exome

AF:

0.00335

Gnomad4 AMR exome

AF:

0.0108

Gnomad4 ASJ exome

AF:

0.0376

Gnomad4 EAS exome

AF:

0.000206

Gnomad4 SAS exome

AF:

0.0153

Gnomad4 FIN exome

AF:

0.0181

Gnomad4 NFE exome

AF:

0.0243

Gnomad4 OTH exome

AF:

0.0197

GnomAD4 genome

AF:

0.0178

AC:

2707

AN:

151976

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1301

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00425

Gnomad4 AMR

AF:

0.0200

Gnomad4 ASJ

AF:

0.0456

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0156

Gnomad4 FIN

AF:

0.0184

Gnomad4 NFE

AF:

0.0254

Gnomad4 OTH

AF:

0.0214

Alfa

AF:

0.0231

Hom.:

Bravo

AF:

0.0175

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0223

AC:

ESP6500AA

AF:

0.00592

AC:

ESP6500EA

AF:

0.0253

AC:

217

ExAC

AF:

0.0182

AC:

2206

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 03, 2017	- -

Peroxisome biogenesis disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Peroxisome biogenesis disorder 8A (Zellweger)

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Peroxisome biogenesis disorder 8A (Zellweger);C3553960:Peroxisome biogenesis disorder 8B

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Likely benign and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.025

.;T;.;.;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.88

D;T;D;D;T

MetaRNN

Benign

0.0037

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.055

N;N;.;.;.

MutationTaster

Benign

0.96

N;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.25

N;N;N;N;N

REVEL

Benign

0.046

Sift

Benign

0.26

T;T;T;T;T

Sift4G

Benign

0.61

T;T;T;T;.

Polyphen

0.0040

B;B;.;.;.

Vest4

0.11

MutPred

0.14

Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);.;.;.;

MPC

0.35

ClinPred

0.0031

GERP RS

3.5

Varity_R

0.038

gMVP

0.24

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