1-160276914-C-T

Variant names:

• chr1-160276914-C-T
• rs41265787
• NM_002857.4:c.*2637G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002857.4(PEX19):​c.*2637G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 449,832 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (63 hom., cov: 32)
  • Exomes 𝑓: 0.028 (200 hom.)
• Consequence: PEX19 NM_002857.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0660

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]

ENSG00000258465 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-160276914-C-T is Benign according to our data. Variant chr1-160276914-C-T is described in ClinVar as [Benign]. Clinvar id is 293191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX19	NM_002857.4	c.*2637G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000368072.10	NP_002848.1
PEX19	NM_001193644.1	c.*2645G>A		3_prime_UTR_variant	Exon 8 of 8		NP_001180573.1
PEX19	NR_036492.2	n.3436G>A		non_coding_transcript_exon_variant	Exon 7 of 7
PEX19	NR_036493.2	n.3460G>A		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX19	ENST00000368072	c.*2637G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_002857.4	ENSP00000357051.5
ENSG00000258465	ENST00000485079.1	c.487+1217G>A		intron_variant	Intron 5 of 6	3		ENSP00000450870.1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3675 AN: 152120 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0211

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.0921

Gnomad SAS AF: 0.0555

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0308 AC: 3981 AN: 129128 Hom.: 90 AF XY: 0.0325 AC XY: 2291 AN XY: 70426

Gnomad AFR exome AF: 0.0231

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0387

Gnomad EAS exome AF: 0.0847

Gnomad SAS exome AF: 0.0516

Gnomad FIN exome AF: 0.0256

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0290

GnomAD4 exome AF: 0.0277 AC: 8255 AN: 297594 Hom.: 200 Cov.: 0 AF XY: 0.0300 AC XY: 5077 AN XY: 169200

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.0194

Gnomad4 ASJ exome AF: 0.0396

Gnomad4 EAS exome AF: 0.0854

Gnomad4 SAS exome AF: 0.0510

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0165

Gnomad4 OTH exome AF: 0.0274

GnomAD4 genome AF: 0.0242 AC: 3678 AN: 152238 Hom.: 63 Cov.: 32 AF XY: 0.0252 AC XY: 1879 AN XY: 74432

Gnomad4 AFR AF: 0.0229

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.0481

Gnomad4 EAS AF: 0.0921

Gnomad4 SAS AF: 0.0554

Gnomad4 FIN AF: 0.0322

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0217 Hom.: 15

Bravo AF: 0.0229

Asia WGS AF: 0.0870 AC: 302 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Peroxisome biogenesis disorder 12A (Zellweger) Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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	-0.66
CADD	Benign	8.5
DANN	Benign	0.83

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: rs41265787; hg19: chr1-160246704;