rs267608255

Positions:

• chr6-136845605-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000318471.5(PEX7):​c.340-10A>G variant causes a splice polypyrimidine tract, 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 ENST00000318471.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.6361
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:2 O:1
• Conservation: PhyloP100: 0.588

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 7787.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=1, Uncertain_significance=2, not_provided=1}. Variant chr6-136845605-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX7	NM_000288.4	c.340-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000318471.5	NP_000279.1
PEX7	NM_001410945.1	c.226-10A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001397874.1
PEX7	XM_006715502.3	c.339+19136A>G		intron_variant			XP_006715565.1
PEX7	XM_047418874.1	c.340-10A>G		splice_polypyrimidine_tract_variant, intron_variant			XP_047274830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5	c.340-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000288.4	ENSP00000315680	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152190 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000127 AC: 32 AN: 251386 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135870

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 SAS 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: 94 AN: 1399318 Hom.: 0 Cov.: 27 AF XY: 0.0000686 AC XY: 48 AN XY: 699958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00229

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000209

Gnomad4 OTH exome AF: 0.000189

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peroxisome biogenesis disorder 9B Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -

Rhizomelic chondrodysplasia punctata type 1 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The PEX7 c.340-10A>G variant is an intron variant that 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 of these individuals had a splice site variant as the second allele, and one had a stop-gained variant. The c.340-10A>G variant was absent from at least 100 control chromosomes and 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 considered to be a variant of unknown significance but suspicious for pathogenicity for rhizomelic chondrodysplasia punctata. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2024	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. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2023	- -

Phytanic acid storage disease Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.54

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

LitVar

Other links and lift over

dbSNP: rs267608255; hg19: chr6-137166743;