rs267608252

Variant names:

• chr6-136822621-C-T
• rs267608252
• NM_000288.4:c.-45C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_000288.4(PEX7):​c.-45C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,353,968 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PEX7 NM_000288.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: -2.09
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-136822621-C-T is Pathogenic according to our data. Variant chr6-136822621-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 38871.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX7	NM_000288.4	c.-45C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	ENST00000318471.5	NP_000279.1
PEX7	NM_000288.4	c.-45C>T		5_prime_UTR_variant	Exon 1 of 10	ENST00000318471.5	NP_000279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5	c.-45C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10	1	NM_000288.4	ENSP00000315680.3
PEX7	ENST00000318471.5	c.-45C>T		5_prime_UTR_variant	Exon 1 of 10	1	NM_000288.4	ENSP00000315680.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000796 AC: 1 AN: 125552 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000170 AC: 23 AN: 1353968 Hom.: 0 Cov.: 28 AF XY: 0.0000149 AC XY: 10 AN XY: 669388

African (AFR) AF: 0.00 AC: 0 AN: 30004

American (AMR) AF: 0.00 AC: 0 AN: 35158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24454

East Asian (EAS) AF: 0.00 AC: 0 AN: 34554

South Asian (SAS) AF: 0.00 AC: 0 AN: 78704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4596

European-Non Finnish (NFE) AF: 0.0000208 AC: 22 AN: 1056744

Other (OTH) AF: 0.0000177 AC: 1 AN: 56438

GnomAD4 genome Cov.: 35

Alfa AF: 0.00156 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 9B Pathogenic:1

Jan 24, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Phytanic acid storage disease Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.1
DANN	Benign	0.88
PhyloP100		-2.1
PromoterAI		0.26	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=103/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267608252; hg19: chr6-137143759;