rs112822975

Positions:

chr7-92511010-C-G

Variant summary

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

The NM_000466.3(PEX1):c.1521G>C(p.Trp507Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,582,928 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 16 hom., cov: 33)

Exomes 𝑓: 0.00070 ( 12 hom. )

Consequence

PEX1
NM_000466.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0520

Variant links:

Genes affected

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

PEX1 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=0.0056954324).

BP6

Variant 7-92511010-C-G is Benign according to our data. Variant chr7-92511010-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 256217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-92511010-C-G is described in Lovd as [Benign]. Variant chr7-92511010-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00735 (1116/151856) while in subpopulation AFR AF= 0.0256 (1061/41404). AF 95% confidence interval is 0.0243. There are 16 homozygotes in gnomad4. There are 527 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3 linkuse as main transcript	c.1521G>C	p.Trp507Cys	missense_variant	8/24	ENST00000248633.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9 linkuse as main transcript	c.1521G>C	p.Trp507Cys	missense_variant	8/24	1	NM_000466.3	P1	O43933-1

Frequencies

GnomAD3 genomes

AF:

0.00732

AC:

1110

AN:

151738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

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:

0.0000294

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00171

AC:

427

AN:

249026

Hom.:

AF XY:

0.00124

AC XY:

168

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.00104

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:

0.0000355

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000695

AC:

995

AN:

1431072

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

403

AN XY:

713792

show subpopulations

Gnomad4 AFR exome

AF:

0.0254

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000829

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.00735

AC:

1116

AN:

151856

Hom.:

Cov.:

AF XY:

0.00710

AC XY:

527

AN XY:

74176

show subpopulations

Gnomad4 AFR

AF:

0.0256

Gnomad4 AMR

AF:

0.00249

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00711

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00835

ESP6500AA

AF:

0.0215

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00208

AC:

252

Asia WGS

AF:

0.00174

AC:

AN:

3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Zellweger spectrum disorders

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2021	- -

Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger)

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

Peroxisome biogenesis disorder 1A (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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.071

.;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.36

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Uncertain

-0.094

MutationAssessor

Benign

1.4

.;L;.

MutationTaster

Benign

0.85

D;D;D;D

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.28

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.85

.;P;.

Vest4

0.42

MutPred

0.41

.;Gain of disorder (P = 0.0441);Gain of disorder (P = 0.0441);

MVP

0.89

MPC

0.25

ClinPred

0.0089

GERP RS

3.6

Varity_R

0.11

gMVP

0.58

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

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