rs267608255

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000288.4(PEX7):c.340-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,551,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000067 ( 0 hom. )

Consequence

PEX7
NM_000288.4 intron

Scores

Splicing: ADA: 0.6361

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:2O:1

Conservation

PhyloP100: 0.588

Publications

4 publications found

Variant links:

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]

PEX7 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 9B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhizomelic chondrodysplasia punctata type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
adult Refsum disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.

PP5

Variant 6-136845605-A-G is Pathogenic according to our data. Variant chr6-136845605-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7787.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
PEX7	NM_000288.4 link	c.340-10A>G	intron_variant	Intron 3 of 9	ENST00000318471.5	NP_000279.1
PEX7	NM_001410945.1 link	c.226-10A>G	intron_variant	Intron 3 of 9		NP_001397874.1
PEX7	XM_006715502.3 link	c.339+19136A>G	intron_variant	Intron 3 of 6		XP_006715565.1
PEX7	XM_047418874.1 link	c.340-10A>G	intron_variant	Intron 3 of 5		XP_047274830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5 link	c.340-10A>G		intron_variant	Intron 3 of 9	1	NM_000288.4	ENSP00000315680.3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000127

AC:

AN:

251386

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000672

AC:

AN:

1399318

Hom.:

Cov.:

AF XY:

0.0000686

AC XY:

AN XY:

699958

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32268

American (AMR)

AF:

0.0000448

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00229

AC:

AN:

25760

East Asian (EAS)

AF:

0.00

AC:

AN:

39388

South Asian (SAS)

AF:

0.00

AC:

AN:

84978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.0000209

AC:

AN:

1054990

Other (OTH)

AF:

0.000189

AC:

AN:

58238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 9B

Pathogenic:3

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 3 of the PEX7 gene. It does not directly change the encoded amino acid sequence of the PEX7 protein. This variant is present in population databases (rs267608255, gnomAD 0.2%). This variant has been observed in individual(s) with rhizomelic chondrodysplasia punctata (PMID: 12325024). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS3-10A>G. ClinVar contains an entry for this variant (Variation ID: 7787). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2002

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 24, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Rhizomelic chondrodysplasia punctata type 1

Pathogenic:2

Feb 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PEX7 c.340-10A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. However, several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' splicing acceptor site, one predicts the variant weakens this site, and three predict the variant creates a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing presumably by nonsense mediated decay, although low levels of normal PEX7 transcript was also detected (Braverman_2002). The variant allele was found at a frequency of 0.00013 in 251386 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PEX7 causing Rhizomelic Chondrodysplasia Punctata Type 1 (0.00013 vs 0.0019), allowing no conclusion about variant significance. c.340-10A>G has been reported in the literature as a compound heterozygous genotype with other pathogenic variants in at-least two individuals, one affected with Rhizomelic Chondrodysplasia Punctata Type 1 and the other with milder features of adult Refsum disease (Braverman_2002). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12325024, 14974078, 25851898). ClinVar contains an entry for this variant (Variation ID: 7787). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Apr 19, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2017

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Phytanic acid storage disease

Uncertain:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.340-10A>G variant has been reported in one study by Braverman et al. (2002) in which it was found in a compound heterozygous state in two unrelated individuals with rhizomelic chondrodysplasia punctata, one with a splice site variant and one with a stop-gained variant as the second allele. The c.340-10A>G variant was absent from at least 100 control chromosomes but is reported at a frequency of 0.00019 in the European (Non-Finnish) population of the Exome Aggregation Consortium. RT-PCR studies demonstrated that the c.340-10A>G variant produced lower levels of mRNA compared to wildtype, which is consistent with the milder disease phenotype in the patients. Based on the available evidence, the c.340-10A>G variant is classified as a variant of unknown significance but suspicious for pathogenicity for rhizomelic chondrodysplasia punctata. -

Inborn genetic diseases

Pathogenic:1

Dec 20, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.340-10A>G intronic alteration results from an A to G substitution 10 nucleotides before coding exon 4 of the PEX7 gene. Based on data from gnomAD, the G allele has an overall frequency of 0.013% (32/251386) total alleles studied. The highest observed frequency was 0.218% (22/10074) of Ashkenazi Jewish alleles. This variant has been identified in conjunction with other PEX7 variants in individuals with features consistent with PEX7-related peroxisome biogenesis disorders (Braverman, 2002). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as likely pathogenic. -

Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B

Pathogenic:1

Jun 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peroxisome biogenesis disorder

Uncertain:1

Feb 05, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.54

PhyloP100

0.59

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.64

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.80

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.80

Position offset: 1

DS_AL_spliceai

0.66

Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over