rs147530802

Variant names:

• chr17-35577920-T-A
• rs147530802
• NM_000286.3:c.102A>T

Variant summary

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

The NM_000286.3(PEX12):​c.102A>T​(p.Arg34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00509 in 1,614,094 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R34K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (41 hom.)
• Consequence: PEX12 NM_000286.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.26
• Publications: 12 publications found

Genes affected

PEX12 (HGNC:8854): (peroxisomal biogenesis factor 12) This gene belongs to the peroxin-12 family. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 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 are a cause of Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

AP2B1 (HGNC:563): (adaptor related protein complex 2 subunit beta 1) The protein encoded by this gene is one of two large chain components of the assembly protein complex 2, which serves to link clathrin to receptors in coated vesicles. The encoded protein is found on the cytoplasmic face of coated vesicles in the plasma membrane. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012576401).
• BP6: Variant 17-35577920-T-A is Benign according to our data. Variant chr17-35577920-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92773.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 = 0.00497 (757/152226) while in subpopulation NFE AF = 0.0062 (422/68012). AF 95% confidence interval is 0.00572. There are 5 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000286.3. 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
	PEX12	NM_000286.3	MANE Select	c.102A>T	p.Arg34Ser	missense	Exon 1 of 3	NP_000277.1	O00623

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX12	ENST00000225873.9	TSL:1 MANE Select	c.102A>T	p.Arg34Ser	missense	Exon 1 of 3	ENSP00000225873.3	O00623
	PEX12	ENST00000586663.2	TSL:1	n.102A>T		non_coding_transcript_exon	Exon 1 of 3	ENSP00000466894.2	A0A075B773
	PEX12	ENST00000585380.1	TSL:4	c.102A>T	p.Arg34Ser	missense	Exon 2 of 3	ENSP00000466280.1	K7ELY8

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 757 AN: 152110 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00620

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00573 AC: 1442 AN: 251440 AF XY: 0.00611

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.00629

Gnomad OTH exome AF: 0.00815

GnomAD4 exome AF: 0.00511 AC: 7464 AN: 1461868 Hom.: 41 Cov.: 31 AF XY: 0.00525 AC XY: 3815 AN XY: 727240

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00362 AC: 162 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 319 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00512 AC: 442 AN: 86258

European-Finnish (FIN) AF: 0.0121 AC: 648 AN: 53420

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.00496 AC: 5517 AN: 1111990

Other (OTH) AF: 0.00498 AC: 301 AN: 60392

GnomAD4 genome AF: 0.00497 AC: 757 AN: 152226 Hom.: 5 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74434

African (AFR) AF: 0.000770 AC: 32 AN: 41532

American (AMR) AF: 0.00393 AC: 60 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4820

European-Finnish (FIN) AF: 0.0142 AC: 151 AN: 10612

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00620 AC: 422 AN: 68012

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00602 Hom.: 3

Bravo AF: 0.00365

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.00574 AC: 697

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	2	Peroxisome biogenesis disorder 3A (Zellweger) (2)
-	-	1	Peroxisome biogenesis disorder type 3B (1)
-	-	1	Peroxisome biogenesis disorder type 3B;C3553929:Peroxisome biogenesis disorder 3A (Zellweger) (1)
-	-	1	PEX12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.015	D
Polyphen		0.92	P
Vest4		0.45
MutPred		0.93		Loss of methylation at R34 (P = 0.0939)
MVP		0.77
MPC		0.46
ClinPred		0.027	T
GERP RS		3.3
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.67
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147530802; hg19: chr17-33904939;