rs1321472

Variant names:

• chr6-136822589-T-C
• rs1321472
• ENST00000865443.1:c.-77T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000367756.8(PEX7):​c.-77T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,362,798 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (6 hom., cov: 35)
  • Exomes 𝑓: 0.00085 (9 hom.)
• Consequence: PEX7 ENST00000367756.8 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.767
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• rhizomelic chondrodysplasia punctata type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Ambry Genetics, G2P
• adult Refsum disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00188 (287/152334) while in subpopulation EAS AF = 0.0253 (131/5174). AF 95% confidence interval is 0.0218. There are 6 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367756.8. 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.-77T>C		upstream_gene	N/A	NP_000279.1	Q6FGN1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX7	ENST00000865443.1		c.-77T>C		5_prime_UTR	Exon 1 of 9	ENSP00000535502.1
	PEX7	ENST00000865442.1		c.-77T>C		5_prime_UTR	Exon 1 of 7	ENSP00000535501.1
	PEX7	ENST00000367756.8	TSL:3	c.-77T>C		5_prime_UTR	Exon 1 of 4	ENSP00000356730.4	Q5TDQ5

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152216 Hom.: 6 Cov.: 35

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000848 AC: 1026 AN: 1210464 Hom.: 9 Cov.: 17 AF XY: 0.000877 AC XY: 530 AN XY: 604606

African (AFR) AF: 0.00 AC: 0 AN: 26658

American (AMR) AF: 0.00352 AC: 122 AN: 34674

Ashkenazi Jewish (ASJ) AF: 0.0000430 AC: 1 AN: 23262

East Asian (EAS) AF: 0.0132 AC: 436 AN: 33016

South Asian (SAS) AF: 0.000461 AC: 35 AN: 75958

European-Finnish (FIN) AF: 0.00685 AC: 227 AN: 33140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4354

European-Non Finnish (NFE) AF: 0.0000862 AC: 80 AN: 928024

Other (OTH) AF: 0.00243 AC: 125 AN: 51378

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152334 Hom.: 6 Cov.: 35 AF XY: 0.00221 AC XY: 165 AN XY: 74498

African (AFR) AF: 0.0000481 AC: 2 AN: 41588

American (AMR) AF: 0.00327 AC: 50 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0253 AC: 131 AN: 5174

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.000824 Hom.: 0

Bravo AF: 0.00168

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Phytanic acid storage disease (1)
-	1	-	Rhizomelic chondrodysplasia punctata (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.61
PhyloP100		-0.77
PromoterAI		-0.24	Neutral
Mutation Taster		=300/0	polymorphism

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: rs1321472; hg19: chr6-137143727;