chr7-92501975-G-T

Variant names:

• chr7-92501975-G-T
• rs10278857
• NM_000466.3:c.2331C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000466.3(PEX1):​c.2331C>A​(p.Gly777Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.919 in 1,613,548 control chromosomes in the GnomAD database, including 681,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G777G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.93 (65997 hom., cov: 32)
  • Exomes 𝑓: 0.92 (615917 hom.)
• Consequence: PEX1 NM_000466.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 2.52
• Publications: 28 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 7-92501975-G-T is Benign according to our data. Variant chr7-92501975-G-T is described in ClinVar as Benign. ClinVar VariationId is 93105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

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.2331C>A	p.Gly777Gly	synonymous	Exon 14 of 24	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.2160C>A	p.Gly720Gly	synonymous	Exon 13 of 23	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.1707C>A	p.Gly569Gly	synonymous	Exon 14 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.2331C>A	p.Gly777Gly	synonymous	Exon 14 of 24	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.2160C>A	p.Gly720Gly	synonymous	Exon 13 of 23	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.2331C>A	p.Gly777Gly	synonymous	Exon 14 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141562 AN: 152186 Hom.: 65939 Cov.: 32

Gnomad AFR AF: 0.976

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.906

Gnomad EAS AF: 0.967

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.913

GnomAD2 exomes AF: 0.921 AC: 231601 AN: 251340 AF XY: 0.920

Gnomad AFR exome AF: 0.976

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 0.968

Gnomad FIN exome AF: 0.866

Gnomad NFE exome AF: 0.912

Gnomad OTH exome AF: 0.913

GnomAD4 exome AF: 0.918 AC: 1341151 AN: 1461244 Hom.: 615917 Cov.: 42 AF XY: 0.918 AC XY: 667282 AN XY: 726982

African (AFR) AF: 0.977 AC: 32690 AN: 33468

American (AMR) AF: 0.940 AC: 42018 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 23724 AN: 26124

East Asian (EAS) AF: 0.964 AC: 38251 AN: 39680

South Asian (SAS) AF: 0.926 AC: 79878 AN: 86236

European-Finnish (FIN) AF: 0.870 AC: 46458 AN: 53416

Middle Eastern (MID) AF: 0.947 AC: 5462 AN: 5768

European-Non Finnish (NFE) AF: 0.915 AC: 1017087 AN: 1111454

Other (OTH) AF: 0.921 AC: 55583 AN: 60376

GnomAD4 genome AF: 0.930 AC: 141681 AN: 152304 Hom.: 65997 Cov.: 32 AF XY: 0.929 AC XY: 69202 AN XY: 74458

African (AFR) AF: 0.976 AC: 40576 AN: 41582

American (AMR) AF: 0.944 AC: 14442 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.906 AC: 3146 AN: 3472

East Asian (EAS) AF: 0.967 AC: 5010 AN: 5180

South Asian (SAS) AF: 0.936 AC: 4517 AN: 4828

European-Finnish (FIN) AF: 0.871 AC: 9234 AN: 10602

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61694 AN: 68026

Other (OTH) AF: 0.914 AC: 1933 AN: 2114

Alfa AF: 0.919 Hom.: 36594

Bravo AF: 0.938

Asia WGS AF: 0.943 AC: 3279 AN: 3476

EpiCase AF: 0.911

EpiControl AF: 0.913

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	-	2	Peroxisome biogenesis disorder 1A (Zellweger) (2)
-	-	2	Zellweger spectrum disorders (2)
-	-	1	Heimler syndrome 1 (1)
-	-	1	Peroxisome biogenesis disorder 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.0
DANN	Benign	0.68
PhyloP100		2.5
Mutation Taster		=96/4	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: rs10278857; hg19: chr7-92131289; COSMIC: COSV108017599; COSMIC: COSV108017599;