1-160278080-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002857.4(PEX19):c.*1471A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 702,516 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (28 hom.)
• Consequence: PEX19 NM_002857.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.421

Genes affected

PEX19 (HGNC:9713): (peroxisomal biogenesis factor 19) This gene is necessary for early peroxisomal biogenesis. It acts both as a cytosolic chaperone and as an import receptor for peroxisomal membrane proteins (PMPs). 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. These disorders have at least 14 complementation groups, with more than one phenotype being observed for some 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), as well as peroxisome biogenesis disorder complementation group 14 (PBD-CG14), which is also known as PBD-CGJ. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-160278080-T-A is Benign according to our data. Variant chr1-160278080-T-A is described in ClinVar as [Benign]. Clinvar id is 874148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0018 (274/152298) while in subpopulation EAS AF= 0.0268 (139/5186). AF 95% confidence interval is 0.0232. There are 4 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX19	NM_002857.4	c.*1471A>T		3_prime_UTR_variant	8/8	ENST00000368072.10
PEX19	NM_001193644.1	c.*1479A>T		3_prime_UTR_variant	8/8
PEX19	NR_036492.2	n.2270A>T		non_coding_transcript_exon_variant	7/7
PEX19	NR_036493.2	n.2294A>T		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX19	ENST00000368072.10	c.*1471A>T		3_prime_UTR_variant	8/8	1	NM_002857.4	P1
PEX19	ENST00000472750.5	c.*2138A>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	1
PEX19	ENST00000467711.5	n.119+51A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152180 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0271

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00555 AC: 726 AN: 130796 Hom.: 4 AF XY: 0.00423 AC XY: 302 AN XY: 71408

Gnomad AFR exome AF: 0.000329

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0215

Gnomad SAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000799

Gnomad OTH exome AF: 0.00399

GnomAD4 exome AF: 0.00375 AC: 2064 AN: 550218 Hom.: 28 Cov.: 0 AF XY: 0.00318 AC XY: 946 AN XY: 297842

Gnomad4 AFR exome AF: 0.000696

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0425

Gnomad4 SAS exome AF: 0.000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000726

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152298 Hom.: 4 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74462

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0268

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.00286

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 12A (Zellweger) Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.7
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs2301299; hg19: chr1-160247870; COSMIC: COSV63619828; COSMIC: COSV63619828;