rs35214605

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-45914138-C-G
• chr11-45914138-C-T
• chr11-45914138-C-A

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

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.760G>C	p.Val254Leu	missense	Exon 8 of 11	NP_004804.2	Q9Y5Y5-1
	PEX16	NM_057174.3		c.760G>C	p.Val254Leu	missense	Exon 8 of 11	NP_476515.2	Q9Y5Y5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX16	ENST00000378750.10	TSL:1 MANE Select	c.760G>C	p.Val254Leu	missense	Exon 8 of 11	ENSP00000368024.5	Q9Y5Y5-1
	PEX16	ENST00000241041.7	TSL:1	c.760G>C	p.Val254Leu	missense	Exon 8 of 11	ENSP00000241041.3	Q9Y5Y5-2
	PEX16	ENST00000905948.1		c.760G>C	p.Val254Leu	missense	Exon 8 of 11	ENSP00000576007.1

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

ALSPAC AF: 0.0223 AC: 86

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Peroxisome biogenesis disorder (1)
-	-	1	Peroxisome biogenesis disorder 8A (Zellweger) (1)
-	-	-	Peroxisome biogenesis disorder 8A (Zellweger);C3553960:Peroxisome biogenesis disorder 8B (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	15
DANN	Benign	0.97
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.055	N
PhyloP100		0.70
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.046
Sift	Benign	0.26	T
Sift4G	Benign	0.61	T
Polyphen		0.0040	B
Vest4		0.11
MutPred		0.14		Loss of sheet (P = 0.0084)
MPC		0.35
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;