11-45909951-G-A

Variant names:

• chr11-45909951-G-A
• rs10838529
• NM_004813.4:c.*303C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004813.4(PEX16):​c.*303C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 788,526 control chromosomes in the GnomAD database, including 170,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (26496 hom., cov: 34)
  • Exomes 𝑓: 0.65 (143617 hom.)
• Consequence: PEX16 NM_004813.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.311
• Publications: 8 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 (BayesDel_noAF=-0.92).
• BP6: Variant 11-45909951-G-A is Benign according to our data. Variant chr11-45909951-G-A is described in ClinVar as [Benign]. Clinvar id is 304781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX16	NM_004813.4	c.*303C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000378750.10	NP_004804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX16	ENST00000378750.10	c.*303C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_004813.4	ENSP00000368024.5
PEX16	ENST00000241041.7	c.*138C>T		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000241041.3
PEX16	ENST00000523721.2	n.*219C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81330 AN: 152092 Hom.: 26501 Cov.: 34

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.595

GnomAD4 exome AF: 0.651 AC: 414088 AN: 636316 Hom.: 143617 Cov.: 8 AF XY: 0.653 AC XY: 220714 AN XY: 337832

African (AFR) AF: 0.176 AC: 3107 AN: 17674

American (AMR) AF: 0.489 AC: 17644 AN: 36086

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 14508 AN: 18894

East Asian (EAS) AF: 0.155 AC: 5244 AN: 33904

South Asian (SAS) AF: 0.585 AC: 36793 AN: 62844

European-Finnish (FIN) AF: 0.696 AC: 24111 AN: 34660

Middle Eastern (MID) AF: 0.708 AC: 1763 AN: 2490

European-Non Finnish (NFE) AF: 0.731 AC: 289733 AN: 396618

Other (OTH) AF: 0.639 AC: 21185 AN: 33146

GnomAD4 genome AF: 0.534 AC: 81321 AN: 152210 Hom.: 26496 Cov.: 34 AF XY: 0.532 AC XY: 39610 AN XY: 74406

African (AFR) AF: 0.173 AC: 7199 AN: 41532

American (AMR) AF: 0.560 AC: 8571 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2688 AN: 3470

East Asian (EAS) AF: 0.193 AC: 1002 AN: 5180

South Asian (SAS) AF: 0.571 AC: 2756 AN: 4826

European-Finnish (FIN) AF: 0.689 AC: 7303 AN: 10606

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49627 AN: 67974

Other (OTH) AF: 0.598 AC: 1262 AN: 2110

Alfa AF: 0.659 Hom.: 61169

Bravo AF: 0.507

Asia WGS AF: 0.398 AC: 1390 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Peroxisome biogenesis disorder 8A (Zellweger) Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.33
DANN	Benign	0.59
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10838529; hg19: chr11-45931502; COSMIC: COSV53796581; COSMIC: COSV53796581;