6-143451039-A-G

Variant names:

• chr6-143451039-A-G
• rs116692495
• NM_003630.3:c.-4A>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_003630.3(PEX3):​c.-4A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000939 in 1,610,084 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (4 hom.)
• Consequence: PEX3 NM_003630.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.780

Genes affected

PEX3 (HGNC:8858): (peroxisomal biogenesis factor 3) The product of this gene is involved in peroxisome biosynthesis and integrity. It assembles membrane vesicles before the matrix proteins are translocated. 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 Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 6-143451039-A-G is Benign according to our data. Variant chr6-143451039-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 259104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00408 (621/152250) while in subpopulation AFR AF = 0.0131 (543/41540). AF 95% confidence interval is 0.0122. There are 5 homozygotes in GnomAd4. There are 288 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX3	NM_003630.3	c.-4A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	ENST00000367591.5	NP_003621.1
PEX3	NM_003630.3	c.-4A>G		5_prime_UTR_variant	Exon 1 of 12	ENST00000367591.5	NP_003621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX3	ENST00000367591.5	c.-4A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	1	NM_003630.3	ENSP00000356563.4
PEX3	ENST00000367591.5	c.-4A>G		5_prime_UTR_variant	Exon 1 of 12	1	NM_003630.3	ENSP00000356563.4
PEX3	ENST00000367592.5	c.-4A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	5		ENSP00000356564.1
PEX3	ENST00000367592.5	c.-4A>G		5_prime_UTR_variant	Exon 1 of 7	5		ENSP00000356564.1

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 619 AN: 152132 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 251466 AF XY: 0.000905

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000611 AC: 891 AN: 1457834 Hom.: 4 Cov.: 30 AF XY: 0.000566 AC XY: 411 AN XY: 725586

African (AFR) AF: 0.0108 AC: 359 AN: 33372

American (AMR) AF: 0.00199 AC: 89 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5752

European-Non Finnish (NFE) AF: 0.000320 AC: 355 AN: 1108316

Other (OTH) AF: 0.00128 AC: 77 AN: 60260

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152250 Hom.: 5 Cov.: 32 AF XY: 0.00387 AC XY: 288 AN XY: 74446

African (AFR) AF: 0.0131 AC: 543 AN: 41540

American (AMR) AF: 0.00327 AC: 50 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68008

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00495

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 10A (Zellweger) Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.88
PhyloP100		0.78
PromoterAI		0.058	Neutral
Mutation Taster		=281/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs116692495; hg19: chr6-143772176;