rs113268723

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-136845652-A-C
• chr6-136845652-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000288.4(PEX7):​c.377A>C​(p.Gln126Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00443 in 1,611,638 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (12 hom.)
• Consequence: PEX7 NM_000288.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 5.55
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015132815).
• BP6: Variant 6-136845652-A-C is Benign according to our data. Variant chr6-136845652-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00363 (553/152282) while in subpopulation NFE AF = 0.00512 (348/68022). AF 95% confidence interval is 0.00467. There are 2 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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>C	p.Gln126Pro	missense	Exon 4 of 10	NP_000279.1
	PEX7	NM_001410945.1		c.263A>C	p.Gln88Pro	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>C	p.Gln126Pro	missense	Exon 4 of 10	ENSP00000315680.3
	PEX7	ENST00000678557.1		c.263A>C	p.Gln88Pro	missense	Exon 4 of 10	ENSP00000502962.1
	PEX7	ENST00000865443.1		c.377A>C	p.Gln126Pro	missense	Exon 4 of 9	ENSP00000535502.1

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152164 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00389 AC: 978 AN: 251428 AF XY: 0.00392

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.00464

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00452 AC: 6589 AN: 1459356 Hom.: 12 Cov.: 29 AF XY: 0.00438 AC XY: 3179 AN XY: 726176

African (AFR) AF: 0.000807 AC: 27 AN: 33444

American (AMR) AF: 0.00174 AC: 78 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00712 AC: 186 AN: 26110

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

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86206

European-Finnish (FIN) AF: 0.0113 AC: 601 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.00485 AC: 5387 AN: 1109740

Other (OTH) AF: 0.00474 AC: 286 AN: 60300

GnomAD4 genome AF: 0.00363 AC: 553 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00383 AC XY: 285 AN XY: 74460

African (AFR) AF: 0.000674 AC: 28 AN: 41558

American (AMR) AF: 0.00176 AC: 27 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00512 AC: 348 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00427 Hom.: 9

Bravo AF: 0.00298

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00380 AC: 461

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00350

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	2	Peroxisome biogenesis disorder 9B (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Phytanic acid storage disease;C1859133:Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B (1)
-	-	1	Rhizomelic chondrodysplasia punctata (1)
-	-	1	Rhizomelic chondrodysplasia punctata type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.062	D
MutationAssessor	Benign	0.25	N
PhyloP100		5.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.62
Sift	Benign	0.10	T
Sift4G	Benign	0.093	T
Polyphen		0.82	P
Vest4		0.77
MVP		1.0
MPC		0.51
ClinPred		0.029	T
GERP RS		5.9
Varity_R		0.46
gMVP		0.69
Mutation Taster		=87/13	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;