11-45914138-C-G

Variant names:

• chr11-45914138-C-G
• rs35214605
• NM_004813.4:c.760G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004813.4(PEX16):​c.760G>C​(p.Val254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,600,486 control chromosomes in the GnomAD database, including 456 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V254M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (19 hom., cov: 33)
  • Exomes 𝑓: 0.022 (437 hom.)
• Consequence: PEX16 NM_004813.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.702
• Publications: 13 publications found

Genes affected

PEX16 (HGNC:8857): (peroxisomal biogenesis factor 16) The protein encoded by this gene is an integral peroxisomal membrane protein. An inactivating nonsense mutation localized to this gene was observed in a patient with Zellweger syndrome of the complementation group CGD/CG9. Expression of this gene product morphologically and biochemically restores the formation of new peroxisomes, suggesting a role in peroxisome organization and biogenesis. Alternative splicing has been observed for this gene and two variants have been described. [provided by RefSeq, Jul 2008]

PEX16 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 8A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• peroxisome biogenesis disorder 8B

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036569238).
• BP6: Variant 11-45914138-C-G is Benign according to our data. Variant chr11-45914138-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 304788.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 = 0.0178 (2707/151976) while in subpopulation NFE AF = 0.0254 (1723/67946). AF 95% confidence interval is 0.0244. There are 19 homozygotes in GnomAd4. There are 1301 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX16	NM_004813.4	c.760G>C	p.Val254Leu	missense_variant	Exon 8 of 11	ENST00000378750.10	NP_004804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX16	ENST00000378750.10	c.760G>C	p.Val254Leu	missense_variant	Exon 8 of 11	1	NM_004813.4	ENSP00000368024.5

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2708 AN: 151856 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00426

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0456

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0194 AC: 4353 AN: 224696 AF XY: 0.0208

Gnomad AFR exome AF: 0.00368

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0389

Gnomad EAS exome AF: 0.000240

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0267

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.0221 AC: 32048 AN: 1448510 Hom.: 437 Cov.: 35 AF XY: 0.0224 AC XY: 16153 AN XY: 719650

African (AFR) AF: 0.00335 AC: 111 AN: 33098

American (AMR) AF: 0.0108 AC: 461 AN: 42814

Ashkenazi Jewish (ASJ) AF: 0.0376 AC: 973 AN: 25850

East Asian (EAS) AF: 0.000206 AC: 8 AN: 38822

South Asian (SAS) AF: 0.0153 AC: 1296 AN: 84682

European-Finnish (FIN) AF: 0.0181 AC: 949 AN: 52310

Middle Eastern (MID) AF: 0.0407 AC: 234 AN: 5750

European-Non Finnish (NFE) AF: 0.0243 AC: 26839 AN: 1105374

Other (OTH) AF: 0.0197 AC: 1177 AN: 59810

GnomAD4 genome AF: 0.0178 AC: 2707 AN: 151976 Hom.: 19 Cov.: 33 AF XY: 0.0175 AC XY: 1301 AN XY: 74316

African (AFR) AF: 0.00425 AC: 176 AN: 41430

American (AMR) AF: 0.0200 AC: 306 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0456 AC: 158 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.0156 AC: 75 AN: 4812

European-Finnish (FIN) AF: 0.0184 AC: 195 AN: 10578

Middle Eastern (MID) AF: 0.0445 AC: 13 AN: 292

European-Non Finnish (NFE) AF: 0.0254 AC: 1723 AN: 67946

Other (OTH) AF: 0.0214 AC: 45 AN: 2102

Alfa AF: 0.0231 Hom.: 46

Bravo AF: 0.0175

TwinsUK AF: 0.0175 AC: 65

ESP6500AA AF: 0.00592 AC: 26

ESP6500EA AF: 0.0253 AC: 217

ExAC AF: 0.0182 AC: 2206

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 23, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 03, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Peroxisome biogenesis disorder Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Peroxisome biogenesis disorder 8A (Zellweger) Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Peroxisome biogenesis disorder 8A (Zellweger);C3553960:Peroxisome biogenesis disorder 8B Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Likely benign and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.0	.;T;.;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.58
LIST_S2	Uncertain	0.88	D;T;D;D;T
MetaRNN	Benign	0.0037	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.055	N;N;.;.;.
PhyloP100		0.70
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.25	N;N;N;N;N
Sift	Benign	0.26	T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;.
Vest4		0.11
ClinPred		0.0031	T
GERP RS		3.5
Varity_R		0.038
gMVP		0.24
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35214605; hg19: chr11-45935689; COSMIC: COSV99060188; COSMIC: COSV99060188;