1-160277395-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002857.4(PEX19):c.*2156C>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 0.49 in 455,818 control chromosomes in the GnomAD database, including 56,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (16145 hom., cov: 32)
  • Exomes 𝑓: 0.51 (39923 hom.)
• Consequence: PEX19 NM_002857.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.465

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=-0.88).
• BP6: Variant 1-160277395-G-C is Benign according to our data. Variant chr1-160277395-G-C is described in ClinVar as [Benign]. Clinvar id is 293196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX19	NM_002857.4	c.*2156C>G		3_prime_UTR_variant	8/8	ENST00000368072.10
PEX19	NM_001193644.1	c.*2164C>G		3_prime_UTR_variant	8/8
PEX19	NR_036492.2	n.2955C>G		non_coding_transcript_exon_variant	7/7
PEX19	NR_036493.2	n.2979C>G		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX19	ENST00000368072.10	c.*2156C>G		3_prime_UTR_variant	8/8	1	NM_002857.4	P1
PEX19	ENST00000472750.5	c.*2823C>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	1
PEX19	ENST00000467711.5	n.120-8C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69175 AN: 151946 Hom.: 16142 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.482

GnomAD3 exomes AF: 0.495 AC: 63464 AN: 128218 Hom.: 16141 AF XY: 0.503 AC XY: 35291 AN XY: 70226

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.481

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.348

Gnomad SAS exome AF: 0.615

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.507

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.507 AC: 154061 AN: 303754 Hom.: 39923 Cov.: 0 AF XY: 0.518 AC XY: 89580 AN XY: 172980

Gnomad4 AFR exome AF: 0.340

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.440

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.610

Gnomad4 FIN exome AF: 0.472

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.490

GnomAD4 genome AF: 0.455 AC: 69214 AN: 152064 Hom.: 16145 Cov.: 32 AF XY: 0.456 AC XY: 33905 AN XY: 74328

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.346

Gnomad4 SAS AF: 0.609

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.504

Gnomad4 OTH AF: 0.483

Alfa AF: 0.466 Hom.: 3007

Bravo AF: 0.448

Asia WGS AF: 0.477 AC: 1657 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

Jan 12, 2018

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.1
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs10594; hg19: chr1-160247185; COSMIC: COSV63619513; COSMIC: COSV63619513;