rs36083022

Positions:

• chr1-10629621-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000356607.9(PEX14):​c.768G>A​(p.Val256=) 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 ENST00000356607.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.239

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX14	NM_004565.3	c.768G>A	p.Val256=	synonymous_variant	9/9	ENST00000356607.9	NP_004556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX14	ENST00000356607.9	c.768G>A	p.Val256=	synonymous_variant	9/9	1	NM_004565.3	ENSP00000349016	P1

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

GnomAD3 exomes AF: 0.0111 AC: 2788 AN: 250992 Hom.: 24 AF XY: 0.0113 AC XY: 1534 AN XY: 135796

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 SAS exome AF: 0.00470

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

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00584

Gnomad4 ASJ exome AF: 0.00543

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00531

Gnomad4 FIN exome AF: 0.00527

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0112

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

Gnomad4 AFR AF: 0.00297

Gnomad4 AMR AF: 0.00805

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00395

Gnomad4 FIN AF: 0.00397

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.0136 Hom.: 11

Bravo AF: 0.0106

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0157

EpiControl AF: 0.0175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 03, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Peroxisome biogenesis disorder, complementation group K Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Peroxisome biogenesis disorder 13A (Zellweger) Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.0
DANN	Benign	0.62

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: rs36083022; hg19: chr1-10689678;