rs115117459

Variant names:

• chr1-10629726-C-T
• rs115117459
• NM_004565.3:c.873C>T

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.873C>T​(p.His291His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,602,506 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (6 hom.)
• Consequence: PEX14 NM_004565.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.57
• Publications: 2 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: G2P, Ambry Genetics, 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=-0.49).
• BP6: Variant 1-10629726-C-T is Benign according to our data. Variant chr1-10629726-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00478 (728/152244) while in subpopulation AFR AF = 0.0163 (678/41538). AF 95% confidence interval is 0.0153. There are 8 homozygotes in GnomAd4. There are 345 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.873C>T	p.His291His	synonymous	Exon 9 of 9	NP_004556.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX14	ENST00000356607.9	TSL:1 MANE Select	c.873C>T	p.His291His	synonymous	Exon 9 of 9	ENSP00000349016.4
	PEX14	ENST00000889280.1		c.870C>T	p.His290His	synonymous	Exon 9 of 9	ENSP00000559339.1
	PEX14	ENST00000923290.1		c.825C>T	p.His275His	synonymous	Exon 8 of 8	ENSP00000593349.1

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 727 AN: 152126 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00136 AC: 303 AN: 223218 AF XY: 0.000951

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000513

Gnomad NFE exome AF: 0.0000406

Gnomad OTH exome AF: 0.000892

GnomAD4 exome AF: 0.000532 AC: 772 AN: 1450262 Hom.: 6 Cov.: 32 AF XY: 0.000457 AC XY: 329 AN XY: 720462

African (AFR) AF: 0.0181 AC: 601 AN: 33132

American (AMR) AF: 0.00134 AC: 57 AN: 42608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25816

East Asian (EAS) AF: 0.00 AC: 0 AN: 39018

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84832

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52596

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5756

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1106528

Other (OTH) AF: 0.00128 AC: 77 AN: 59976

GnomAD4 genome AF: 0.00478 AC: 728 AN: 152244 Hom.: 8 Cov.: 32 AF XY: 0.00464 AC XY: 345 AN XY: 74430

African (AFR) AF: 0.0163 AC: 678 AN: 41538

American (AMR) AF: 0.00235 AC: 36 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68028

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00294 Hom.: 0

Bravo AF: 0.00513

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.49
CADD	Benign	8.5
DANN	Benign	0.47
PhyloP100		1.6
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: rs115117459; hg19: chr1-10689783; COSMIC: COSV63064022;