rs141133579

Variant names:

• chr1-160280067-T-C
• rs141133579
• NM_002857.4:c.771+3A>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_002857.4(PEX19):​c.771+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00554 in 1,613,042 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (29 hom.)
• Consequence: PEX19 NM_002857.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002355
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.323
• Publications: 1 publications found

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:):

DCAF8-DT (HGNC:55792): (DCAF8 divergent transcript)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-160280067-T-C is Benign according to our data. Variant chr1-160280067-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00412 (627/152306) while in subpopulation NFE AF = 0.00562 (382/68006). AF 95% confidence interval is 0.00515. There are 5 homozygotes in GnomAd4. There are 331 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002857.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX19	NM_002857.4	MANE Select	c.771+3A>G		splice_region intron	N/A	NP_002848.1	A0A0S2Z497
	PEX19	NM_001193644.1		c.771+3A>G		splice_region intron	N/A	NP_001180573.1	P40855
	PEX19	NR_036492.2		n.670+3A>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX19	ENST00000368072.10	TSL:1 MANE Select	c.771+3A>G		splice_region intron	N/A	ENSP00000357051.5	P40855-1
	ENSG00000258465	ENST00000485079.1	TSL:3	c.381+3A>G		splice_region intron	N/A	ENSP00000450870.1	H0YJ60
	PEX19	ENST00000472750.5	TSL:1	n.*538+3A>G		splice_region intron	N/A	ENSP00000434633.1	P40855-6

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 627 AN: 152188 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00562

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00471 AC: 1182 AN: 250936 AF XY: 0.00491

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.00623

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00569 AC: 8313 AN: 1460736 Hom.: 29 Cov.: 32 AF XY: 0.00573 AC XY: 4162 AN XY: 726730

African (AFR) AF: 0.000837 AC: 28 AN: 33442

American (AMR) AF: 0.00195 AC: 87 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00128 AC: 110 AN: 86224

European-Finnish (FIN) AF: 0.0161 AC: 859 AN: 53414

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5712

European-Non Finnish (NFE) AF: 0.00626 AC: 6951 AN: 1111056

Other (OTH) AF: 0.00409 AC: 247 AN: 60348

GnomAD4 genome AF: 0.00412 AC: 627 AN: 152306 Hom.: 5 Cov.: 32 AF XY: 0.00444 AC XY: 331 AN XY: 74478

African (AFR) AF: 0.000962 AC: 40 AN: 41572

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.0152 AC: 161 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00562 AC: 382 AN: 68006

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00486 Hom.: 2

Bravo AF: 0.00327

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Peroxisome biogenesis disorder 12A (Zellweger) (2)
-	-	1	not specified (1)
-	-	1	PEX19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.1
DANN	Benign	0.59
PhyloP100		-0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.018
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

Other links and lift over

dbSNP: rs141133579; hg19: chr1-160249857;