rs149729088

Variant names:

• chr7-92518145-T-C
• rs149729088
• NM_000466.3:c.468A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-92518145-T-C
• chr7-92518145-T-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000466.3(PEX1):​c.468A>G​(p.Gln156Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,611,002 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: PEX1 NM_000466.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.86
• Publications: 0 publications found

Genes affected

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

PEX1 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 1A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, Myriad Women’s Health
• Heimler syndrome 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Ambry Genetics
• peroxisome biogenesis disorder 1B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000244055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 7-92518145-T-C is Benign according to our data. Variant chr7-92518145-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285002.
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00249 (379/152230) while in subpopulation AFR AF = 0.00855 (355/41534). AF 95% confidence interval is 0.00781. There are 2 homozygotes in GnomAd4. There are 185 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_000466.3. 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
	PEX1	NM_000466.3	MANE Select	c.468A>G	p.Gln156Gln	synonymous	Exon 4 of 24	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.468A>G	p.Gln156Gln	synonymous	Exon 4 of 23	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.-157A>G		5_prime_UTR	Exon 4 of 24	NP_001269607.1	B4DER6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	ENST00000248633.9	TSL:1 MANE Select	c.468A>G	p.Gln156Gln	synonymous	Exon 4 of 24	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.468A>G	p.Gln156Gln	synonymous	Exon 4 of 23	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.468A>G	p.Gln156Gln	synonymous	Exon 4 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152112 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00852

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000553 AC: 139 AN: 251388 AF XY: 0.000375

Gnomad AFR exome AF: 0.00750

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000288 AC: 420 AN: 1458772 Hom.: 2 Cov.: 30 AF XY: 0.000233 AC XY: 169 AN XY: 725986

African (AFR) AF: 0.0103 AC: 344 AN: 33402

American (AMR) AF: 0.000604 AC: 27 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109238

Other (OTH) AF: 0.000647 AC: 39 AN: 60292

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152230 Hom.: 2 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74436

African (AFR) AF: 0.00855 AC: 355 AN: 41534

American (AMR) AF: 0.000981 AC: 15 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00306

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Zellweger spectrum disorders (2)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Peroxisome biogenesis disorder 1A (Zellweger) (1)
-	-	1	PEX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.24
DANN	Benign	0.19
PhyloP100		-1.9

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: rs149729088; hg19: chr7-92147459;