rs36083022

Variant names:

• chr1-10629621-G-A
• rs36083022
• NM_004565.3:c.768G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004565.3(PEX14):​c.768G>A​(p.Val256Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,660 control chromosomes in the GnomAD database, including 193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (8 hom., cov: 32)
  • Exomes 𝑓: 0.015 (185 hom.)
• Consequence: PEX14 NM_004565.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.239
• Publications: 3 publications found

Genes affected

PEX14 (HGNC:8856): (peroxisomal biogenesis factor 14) This gene encodes an essential component of the peroxisomal import machinery. The protein is integrated into peroxisome membranes with its C-terminus exposed to the cytosol, and interacts with the cytosolic receptor for proteins containing a PTS1 peroxisomal targeting signal. The protein also functions as a transcriptional corepressor and interacts with a histone deacetylase. A mutation in this gene results in one form of Zellweger syndrome. [provided by RefSeq, Jul 2008]

PEX14 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 13A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-10629621-G-A is Benign according to our data. Variant chr1-10629621-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.239 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1573/152000) while in subpopulation NFE AF = 0.0179 (1216/67950). AF 95% confidence interval is 0.0171. There are 8 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004565.3. 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
	PEX14	NM_004565.3	MANE Select	c.768G>A	p.Val256Val	synonymous	Exon 9 of 9	NP_004556.1	O75381-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX14	ENST00000356607.9	TSL:1 MANE Select	c.768G>A	p.Val256Val	synonymous	Exon 9 of 9	ENSP00000349016.4	O75381-1
	PEX14	ENST00000889280.1		c.765G>A	p.Val255Val	synonymous	Exon 9 of 9	ENSP00000559339.1
	PEX14	ENST00000923290.1		c.720G>A	p.Val240Val	synonymous	Exon 8 of 8	ENSP00000593349.1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1577 AN: 151884 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00437

Gnomad FIN AF: 0.00397

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.00767

GnomAD2 exomes AF: 0.0111 AC: 2788 AN: 250992 AF XY: 0.0113

Gnomad AFR exome AF: 0.00296

Gnomad AMR exome AF: 0.00532

Gnomad ASJ exome AF: 0.00567

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00485

Gnomad NFE exome AF: 0.0191

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0148 AC: 21698 AN: 1461660 Hom.: 185 Cov.: 32 AF XY: 0.0146 AC XY: 10584 AN XY: 727128

African (AFR) AF: 0.00248 AC: 83 AN: 33480

American (AMR) AF: 0.00584 AC: 261 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 142 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00531 AC: 458 AN: 86254

European-Finnish (FIN) AF: 0.00527 AC: 281 AN: 53334

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.0178 AC: 19741 AN: 1111876

Other (OTH) AF: 0.0112 AC: 675 AN: 60390

GnomAD4 genome AF: 0.0103 AC: 1573 AN: 152000 Hom.: 8 Cov.: 32 AF XY: 0.00950 AC XY: 706 AN XY: 74300

African (AFR) AF: 0.00297 AC: 123 AN: 41468

American (AMR) AF: 0.00805 AC: 123 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4806

European-Finnish (FIN) AF: 0.00397 AC: 42 AN: 10582

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0179 AC: 1216 AN: 67950

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.0157 Hom.: 44

Bravo AF: 0.0106

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0157

EpiControl AF: 0.0175

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Peroxisome biogenesis disorder 13A (Zellweger) (1)
-	-	1	Peroxisome biogenesis disorder, complementation group K (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.0
DANN	Benign	0.62
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs36083022; hg19: chr1-10689678;