1-160277494-A-C

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.*2057T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 455,832 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (46 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (15 hom.)
• Consequence: PEX19 NM_002857.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.101

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=-0.93).
• BP6: Variant 1-160277494-A-C is Benign according to our data. Variant chr1-160277494-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 293199.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2113/152296) while in subpopulation AFR AF= 0.0421 (1752/41570). AF 95% confidence interval is 0.0405. There are 46 homozygotes in gnomad4. There are 1022 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX19	NM_002857.4	c.*2057T>G		3_prime_UTR_variant	8/8	ENST00000368072.10
PEX19	NM_001193644.1	c.*2065T>G		3_prime_UTR_variant	8/8
PEX19	NR_036492.2	n.2856T>G		non_coding_transcript_exon_variant	7/7
PEX19	NR_036493.2	n.2880T>G		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX19	ENST00000368072.10	c.*2057T>G		3_prime_UTR_variant	8/8	1	NM_002857.4	P1
PEX19	ENST00000472750.5	c.*2724T>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	1
PEX19	ENST00000467711.5	n.120-107T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2116 AN: 152178 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00823 AC: 1072 AN: 130284 Hom.: 11 AF XY: 0.00646 AC XY: 460 AN XY: 71170

Gnomad AFR exome AF: 0.0429

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0224

Gnomad SAS exome AF: 0.000491

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000303

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00445 AC: 1351 AN: 303536 Hom.: 15 Cov.: 0 AF XY: 0.00348 AC XY: 602 AN XY: 172888

Gnomad4 AFR exome AF: 0.0419

Gnomad4 AMR exome AF: 0.0219

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0269

Gnomad4 SAS exome AF: 0.000636

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.00479

GnomAD4 genome AF: 0.0139 AC: 2113 AN: 152296 Hom.: 46 Cov.: 32 AF XY: 0.0137 AC XY: 1022 AN XY: 74468

Gnomad4 AFR AF: 0.0421

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0278

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00544 Hom.: 7

Bravo AF: 0.0173

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 12A (Zellweger) Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	1.2
Dann	Benign	0.51

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: rs56089807; hg19: chr1-160247284;