rs61753238

Positions:

• chr6-136822785-C-A
• chr6-136822785-C-G
• chr6-136822785-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000288.4(PEX7):​c.120C>A​(p.Tyr40Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000835 in 1,198,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y40Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: PEX7 NM_000288.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX7	NM_000288.4	c.120C>A	p.Tyr40Ter	stop_gained	1/10	ENST00000318471.5
PEX7	XM_006715502.3	c.120C>A	p.Tyr40Ter	stop_gained	1/7
PEX7	XM_047418874.1	c.120C>A	p.Tyr40Ter	stop_gained	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX7	ENST00000318471.5	c.120C>A	p.Tyr40Ter	stop_gained	1/10	1	NM_000288.4	P1
PEX7	ENST00000367756.8	c.120C>A	p.Tyr40Ter	stop_gained	1/4	3
PEX7	ENST00000541292.6	c.120C>A	p.Tyr40Ter	stop_gained, NMD_transcript_variant	1/11	5
PEX7	ENST00000678593.1	c.120C>A	p.Tyr40Ter	stop_gained, NMD_transcript_variant	1/8

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.0000416 AC: 1 AN: 24010 Hom.: 0 AF XY: 0.0000655 AC XY: 1 AN XY: 15258

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1198062 Hom.: 0 Cov.: 32 AF XY: 0.00000171 AC XY: 1 AN XY: 583098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.79
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61753238; hg19: chr6-137143923;