chr7-92510952-T-C

Variant names:

• chr7-92510952-T-C
• rs144942544
• NM_000466.3:c.1579A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000466.3(PEX1):​c.1579A>G​(p.Thr527Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,459,962 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. T527T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15
• Conservation: PhyloP100: 1.97
• Publications: 7 publications found

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]

PEX1 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 1A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, Myriad Women’s Health
• Heimler syndrome 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• peroxisome biogenesis disorder 1B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000244055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007453084).
• BP6: Variant 7-92510952-T-C is Benign according to our data. Variant chr7-92510952-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 493456.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00218 (332/152358) while in subpopulation NFE AF = 0.00362 (246/68032). AF 95% confidence interval is 0.00324. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000466.3. 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
	PEX1	NM_000466.3	MANE Select	c.1579A>G	p.Thr527Ala	missense	Exon 8 of 24	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.1579A>G	p.Thr527Ala	missense	Exon 8 of 23	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.955A>G	p.Thr319Ala	missense	Exon 8 of 24	NP_001269607.1	B4DER6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	ENST00000248633.9	TSL:1 MANE Select	c.1579A>G	p.Thr527Ala	missense	Exon 8 of 24	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.1579A>G	p.Thr527Ala	missense	Exon 8 of 23	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.1579A>G	p.Thr527Ala	missense	Exon 8 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 334 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00206 AC: 512 AN: 248932 AF XY: 0.00222

Gnomad AFR exome AF: 0.000515

Gnomad AMR exome AF: 0.000931

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000833

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00249 AC: 3260 AN: 1307604 Hom.: 6 Cov.: 21 AF XY: 0.00249 AC XY: 1643 AN XY: 658608

African (AFR) AF: 0.000393 AC: 12 AN: 30546

American (AMR) AF: 0.00104 AC: 46 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 38846

South Asian (SAS) AF: 0.00166 AC: 137 AN: 82432

European-Finnish (FIN) AF: 0.000657 AC: 35 AN: 53268

Middle Eastern (MID) AF: 0.00459 AC: 25 AN: 5448

European-Non Finnish (NFE) AF: 0.00294 AC: 2860 AN: 972418

Other (OTH) AF: 0.00256 AC: 141 AN: 55088

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00197 AC XY: 147 AN XY: 74504

African (AFR) AF: 0.000505 AC: 21 AN: 41584

American (AMR) AF: 0.00131 AC: 20 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4834

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00362 AC: 246 AN: 68032

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00305 Hom.: 2

Bravo AF: 0.00240

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000467 AC: 2

ESP6500EA AF: 0.00342 AC: 29

ExAC AF: 0.00201 AC: 244

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	-	2	not specified (2)
-	1	1	Peroxisome biogenesis disorder 1A (Zellweger) (2)
-	1	1	Peroxisome biogenesis disorder 1B (2)
-	-	2	Zellweger spectrum disorders (2)
-	-	1	Heimler syndrome 1 (1)
-	-	1	PEX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.13	T
Sift4G	Benign	0.71	T
Polyphen		0.17	B
Vest4		0.17
MVP		0.78
MPC		0.18
ClinPred		0.017	T
GERP RS		0.89
Varity_R		0.045
gMVP		0.37
Mutation Taster		=94/6	polymorphism

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: rs144942544; hg19: chr7-92140266;