rs113268723

Positions:

• chr6-136845652-A-C

Variant summary

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

The NM_000288.4(PEX7):​c.377A>C​(p.Gln126Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00443 in 1,611,638 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (12 hom.)
• Consequence: PEX7 NM_000288.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 5.55

Genes affected

PEX7 (HGNC:8860): (peroxisomal biogenesis factor 7) This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015132815).
• BP6: Variant 6-136845652-A-C is Benign according to our data. Variant chr6-136845652-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 255746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-136845652-A-C is described in Lovd as [Benign]. Variant chr6-136845652-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00363 (553/152282) while in subpopulation NFE AF= 0.00512 (348/68022). AF 95% confidence interval is 0.00467. There are 2 homozygotes in gnomad4. There are 285 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX7	NM_000288.4	c.377A>C	p.Gln126Pro	missense_variant	4/10	ENST00000318471.5
PEX7	NM_001410945.1	c.263A>C	p.Gln88Pro	missense_variant	4/10
PEX7	XM_047418874.1	c.377A>C	p.Gln126Pro	missense_variant	4/6
PEX7	XM_006715502.3	c.339+19183A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX7	ENST00000318471.5	c.377A>C	p.Gln126Pro	missense_variant	4/10	1	NM_000288.4	P1

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00389 AC: 978 AN: 251428 Hom.: 3 AF XY: 0.00392 AC XY: 533 AN XY: 135890

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00452 AC: 6589 AN: 1459356 Hom.: 12 Cov.: 29 AF XY: 0.00438 AC XY: 3179 AN XY: 726176

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.00712

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0113

Gnomad4 NFE exome AF: 0.00485

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00383 AC XY: 285 AN XY: 74460

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.00512

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00438 Hom.: 3

Bravo AF: 0.00298

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00380 AC: 461

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00350

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	PEX7: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 03, 2023	- -
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	Jul 01, 2024	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 29, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 10, 2016	- -

Peroxisome biogenesis disorder 9B Benign:2

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Rhizomelic chondrodysplasia punctata type 1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Phytanic acid storage disease;C1859133:Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Rhizomelic chondrodysplasia punctata Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 10, 2017

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.015	T;T
MetaSVM	Uncertain	0.062	D
MutationAssessor	Benign	0.25	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.62
Sift	Benign	0.10	T;T
Sift4G	Benign	0.093	T;T
Polyphen		0.82	.;P
Vest4		0.77
MVP		1.0
MPC		0.51
ClinPred		0.029	T
GERP RS		5.9
Varity_R		0.46
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113268723; hg19: chr6-137166790;