11-45915755-C-T

Variant names:

• chr11-45915755-C-T
• rs11553094
• NM_004813.4:c.307G>A

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.307G>A​(p.Val103Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,613,992 control chromosomes in the GnomAD database, including 634 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. V103L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (47 hom., cov: 31)
  • Exomes 𝑓: 0.026 (587 hom.)
• Consequence: PEX16 NM_004813.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.03
• Publications: 14 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=0.010723561).
• BP6: Variant 11-45915755-C-T is Benign according to our data. Variant chr11-45915755-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004813.4. 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
	PEX16	NM_004813.4	MANE Select	c.307G>A	p.Val103Met	missense	Exon 4 of 11	NP_004804.2
	PEX16	NM_057174.3		c.307G>A	p.Val103Met	missense	Exon 4 of 11	NP_476515.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX16	ENST00000378750.10	TSL:1 MANE Select	c.307G>A	p.Val103Met	missense	Exon 4 of 11	ENSP00000368024.5
	PEX16	ENST00000241041.7	TSL:1	c.307G>A	p.Val103Met	missense	Exon 4 of 11	ENSP00000241041.3
	PEX16	ENST00000905948.1		c.307G>A	p.Val103Met	missense	Exon 4 of 11	ENSP00000576007.1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3024 AN: 152088 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.00488

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0235

GnomAD2 exomes AF: 0.0227 AC: 5714 AN: 251380 AF XY: 0.0240

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0220

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.0329

GnomAD4 exome AF: 0.0263 AC: 38434 AN: 1461786 Hom.: 587 Cov.: 36 AF XY: 0.0265 AC XY: 19299 AN XY: 727200

African (AFR) AF: 0.00574 AC: 192 AN: 33478

American (AMR) AF: 0.0163 AC: 730 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 551 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0233 AC: 2011 AN: 86256

European-Finnish (FIN) AF: 0.0256 AC: 1367 AN: 53400

Middle Eastern (MID) AF: 0.0593 AC: 342 AN: 5768

European-Non Finnish (NFE) AF: 0.0284 AC: 31608 AN: 1111928

Other (OTH) AF: 0.0270 AC: 1631 AN: 60396

GnomAD4 genome AF: 0.0199 AC: 3023 AN: 152206 Hom.: 47 Cov.: 31 AF XY: 0.0197 AC XY: 1463 AN XY: 74396

African (AFR) AF: 0.00486 AC: 202 AN: 41546

American (AMR) AF: 0.0196 AC: 299 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5140

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4818

European-Finnish (FIN) AF: 0.0276 AC: 293 AN: 10610

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0294 AC: 2001 AN: 68018

Other (OTH) AF: 0.0232 AC: 49 AN: 2110

Alfa AF: 0.0253 Hom.: 217

Bravo AF: 0.0190

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0285 AC: 110

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0270 AC: 232

ExAC AF: 0.0234 AC: 2837

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0328

EpiControl AF: 0.0299

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Peroxisome biogenesis disorder (1)
-	-	1	Peroxisome biogenesis disorder 8A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.058
Sift	Benign	0.041	D
Sift4G	Benign	0.086	T
Polyphen		0.71	P
Vest4		0.17
MPC		0.47
ClinPred		0.012	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.25
Mutation Taster		=87/13	polymorphism (auto)

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: rs11553094; hg19: chr11-45937306;