rs79435202

chr11-45910096-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000241041.7(PEX16):c.1034A>C(p.His345Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,611,204 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H345H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (35 hom.)
• Consequence: PEX16 ENST00000241041.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.937

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002622664).
• BP6: Variant 11-45910096-T-G is Benign according to our data. Variant chr11-45910096-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 304783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-45910096-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2037/152226) while in subpopulation AFR AF= 0.045 (1870/41536). AF 95% confidence interval is 0.0433. There are 40 homozygotes in gnomad4. There are 951 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX16	NM_004813.4	c.*158A>C		3_prime_UTR_variant	11/11	ENST00000378750.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX16	ENST00000241041.7	c.1034A>C	p.His345Pro	missense_variant	11/11	1
PEX16	ENST00000378750.10	c.*158A>C		3_prime_UTR_variant	11/11	1	NM_004813.4	P1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2028 AN: 152108 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00403 AC: 1008 AN: 250066 Hom.: 24 AF XY: 0.00290 AC XY: 393 AN XY: 135422

Gnomad AFR exome AF: 0.0470

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00191 AC: 2785 AN: 1458978 Hom.: 35 Cov.: 32 AF XY: 0.00174 AC XY: 1261 AN XY: 725812

Gnomad4 AFR exome AF: 0.0472

Gnomad4 AMR exome AF: 0.00432

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000618

Gnomad4 OTH exome AF: 0.00447

GnomAD4 genome AF: 0.0134 AC: 2037 AN: 152226 Hom.: 40 Cov.: 33 AF XY: 0.0128 AC XY: 951 AN XY: 74434

Gnomad4 AFR AF: 0.0450

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00313 Hom.: 7

Bravo AF: 0.0152

ESP6500AA AF: 0.0350 AC: 154

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00449 AC: 545

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

Peroxisome biogenesis disorder 8A (Zellweger) Benign:1

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	4.1
Dann	Benign	0.37
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00071	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.049
Sift	Benign	0.40	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.11
MPC		0.55
ClinPred		0.00079	T
GERP RS		2.9
gMVP		0.56

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs79435202; hg19: chr11-45931647;