NM_000288.4:c.122G>T

Variant names:

• chr6-136822787-G-T
• rs61753239
• NM_000288.4:c.122G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000288.4(PEX7):​c.122G>T​(p.Gly41Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEX7 NM_000288.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.02
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000288.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX7	NM_000288.4	MANE Select	c.122G>T	p.Gly41Val	missense	Exon 1 of 10	NP_000279.1
	PEX7	NM_001410945.1		c.-577G>T		upstream_gene	N/A	NP_001397874.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX7	ENST00000318471.5	TSL:1 MANE Select	c.122G>T	p.Gly41Val	missense	Exon 1 of 10	ENSP00000315680.3
	PEX7	ENST00000367756.8	TSL:3	c.122G>T	p.Gly41Val	missense	Exon 1 of 4	ENSP00000356730.4
	PEX7	ENST00000541292.6	TSL:5	n.122G>T		non_coding_transcript_exon	Exon 1 of 11	ENSP00000441004.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1192376 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 579710

African (AFR) AF: 0.00 AC: 0 AN: 23912

American (AMR) AF: 0.00 AC: 0 AN: 11608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17306

East Asian (EAS) AF: 0.00 AC: 0 AN: 26408

South Asian (SAS) AF: 0.00 AC: 0 AN: 47432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3388

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 985220

Other (OTH) AF: 0.00 AC: 0 AN: 48548

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 1 Uncertain:1

Jan 22, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.86		Gain of sheet (P = 0.0028)
MVP		1.0
MPC		0.63
ClinPred		1.0	D
GERP RS		4.4
PromoterAI		0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.81
Mutation Taster		=6/94	disease causing

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: rs61753239; hg19: chr6-137143925;