rs200154696

Variant names:

• chr1-10475010-G-A
• rs200154696
• NM_004565.3:c.36+8G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_004565.3(PEX14):​c.36+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,608,126 control chromosomes in the GnomAD database, including 6 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: PEX14 NM_004565.3 splice_region, intron
• Scores: Splicing: ADA: 0.07612
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.86
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 1-10475010-G-A is Benign according to our data. Variant chr1-10475010-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259436.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00109 (166/152350) while in subpopulation AMR AF = 0.00209 (32/15308). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX14	NM_004565.3	MANE Select	c.36+8G>A		splice_region intron	N/A	NP_004556.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX14	ENST00000356607.9	TSL:1 MANE Select	c.36+8G>A		splice_region intron	N/A	ENSP00000349016.4
	PEX14	ENST00000491661.2	TSL:2	c.21+8G>A		splice_region intron	N/A	ENSP00000465473.1
	PEX14	ENST00000472851.1	TSL:3	n.293+2430G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00151 AC: 356 AN: 236358 AF XY: 0.00153

Gnomad AFR exome AF: 0.0000688

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000875

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00108 AC: 1571 AN: 1455776 Hom.: 6 Cov.: 30 AF XY: 0.00110 AC XY: 794 AN XY: 723656

African (AFR) AF: 0.000808 AC: 27 AN: 33410

American (AMR) AF: 0.00114 AC: 50 AN: 43986

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 557 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39518

South Asian (SAS) AF: 0.000400 AC: 34 AN: 85014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52744

Middle Eastern (MID) AF: 0.0179 AC: 103 AN: 5742

European-Non Finnish (NFE) AF: 0.000564 AC: 626 AN: 1109288

Other (OTH) AF: 0.00289 AC: 174 AN: 60116

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.00118 AC XY: 88 AN XY: 74492

African (AFR) AF: 0.000192 AC: 8 AN: 41594

American (AMR) AF: 0.00209 AC: 32 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00250 Hom.: 0

Bravo AF: 0.00123

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	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	-0.26
CADD	Benign	17
DANN	Uncertain	0.97
PhyloP100		2.9
PromoterAI		0.085	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.076
dbscSNV1_RF	Benign	0.15
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: rs200154696; hg19: chr1-10535067;