6-136845652-A-G

Variant names:

• chr6-136845652-A-G
• rs113268723
• NM_000288.4:c.377A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000288.4(PEX7):​c.377A>G​(p.Gln126Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q126P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PEX7 NM_000288.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.55
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4039064).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX7	NM_000288.4	MANE Select	c.377A>G	p.Gln126Arg	missense	Exon 4 of 10	NP_000279.1
	PEX7	NM_001410945.1		c.263A>G	p.Gln88Arg	missense	Exon 4 of 10	NP_001397874.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX7	ENST00000318471.5	TSL:1 MANE Select	c.377A>G	p.Gln126Arg	missense	Exon 4 of 10	ENSP00000315680.3
	PEX7	ENST00000678557.1		c.263A>G	p.Gln88Arg	missense	Exon 4 of 10	ENSP00000502962.1
	PEX7	ENST00000865443.1		c.377A>G	p.Gln126Arg	missense	Exon 4 of 9	ENSP00000535502.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459428 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726208

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109808

Other (OTH) AF: 0.00 AC: 0 AN: 60302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.17	N
PhyloP100		5.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.37
Sift	Benign	0.34	T
Sift4G	Benign	0.54	T
Polyphen		0.69	P
Vest4		0.48
MutPred		0.54		Gain of MoRF binding (P = 0.033)
MVP		0.99
MPC		0.31
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.19
gMVP		0.47
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113268723; hg19: chr6-137166790;