rs773922257

chr7-92517850-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000466.3(PEX1):c.665C>T(p.Thr222Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,543,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T222T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.15

Genes affected

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09309521).
• BP6: Variant 7-92517850-G-A is Benign according to our data. Variant chr7-92517850-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197673.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX1	NM_000466.3	c.665C>T	p.Thr222Ile	missense_variant	5/24	ENST00000248633.9
PEX1	NM_001282677.2	c.665C>T	p.Thr222Ile	missense_variant	5/23
PEX1	NM_001282678.2	c.41C>T	p.Thr14Ile	missense_variant	5/24
PEX1	XM_047420472.1	c.665C>T	p.Thr222Ile	missense_variant	5/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX1	ENST00000248633.9	c.665C>T	p.Thr222Ile	missense_variant	5/24	1	NM_000466.3	P1
PEX1	ENST00000428214.5	c.665C>T	p.Thr222Ile	missense_variant	5/23	1
PEX1	ENST00000438045.5	c.274-3883C>T		intron_variant		2
PEX1	ENST00000484913.5	n.704C>T		non_coding_transcript_exon_variant	5/24	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000525 AC: 1 AN: 190414 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 101000

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 20 AN: 1390812 Hom.: 0 Cov.: 33 AF XY: 0.0000117 AC XY: 8 AN XY: 685802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 12, 2014

- -

Zellweger spectrum disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	12
Dann	Benign	0.94
DEOGEN2	Benign	0.052	T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.093	T;T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.16
Sift	Benign	0.052	T;D
Sift4G	Benign	0.20	T;T
Polyphen		0.23	B;.
Vest4		0.26
MVP		0.80
MPC		0.18
ClinPred		0.072	T
GERP RS		3.1
Varity_R		0.055
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs773922257; hg19: chr7-92147164;