Genetic Variant NM_000287.4:c.207C>T (chr6-42978944-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000287.4(PEX6):c.207C>T(p.Pro69Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,494,790 control chromosomes in the GnomAD database, including 187 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. P69P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.021 ( 95 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 92 hom. )

Consequence

PEX6
NM_000287.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.67

Publications

1 publications found

Variant links:

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 4A (Zellweger)
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
peroxisome biogenesis disorder 4B
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Heimler syndrome 2
Inheritance: AR Classification: MODERATE Submitted by: G2P
autosomal recessive cerebellar ataxia-blindness-deafness syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Zellweger spectrum disorders
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 6-42978944-G-A is Benign according to our data. Variant chr6-42978944-G-A is described in ClinVar as Benign. ClinVar VariationId is 92782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.67 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0714 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000287.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX6	NM_000287.4	MANE Select	c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 17	NP_000278.3
PEX6	NM_001316313.2		c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 17	NP_001303242.1	Q13608-3
PEX6	NR_133009.2		n.238C>T		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX6	ENST00000304611.13	TSL:1 MANE Select	c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 17	ENSP00000303511.8	Q13608-1
PEX6	ENST00000244546.4	TSL:1	c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 15	ENSP00000244546.4	Q13608-2
PEX6	ENST00000858656.1		c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3229

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0738

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.00227

AC:

212

AN:

93208

AF XY:

0.00203

show subpopulations

Gnomad AFR exome

AF:

0.0896

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.00237

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000318

Gnomad OTH exome

AF:

0.00355

GnomAD4 exome

AF:

0.00195

AC:

2615

AN:

1342622

Hom.:

Cov.:

AF XY:

0.00173

AC XY:

1149

AN XY:

662296

show subpopulations

African (AFR)

AF:

0.0759

AC:

2062

AN:

27170

American (AMR)

AF:

0.00356

AC:

107

AN:

30036

Ashkenazi Jewish (ASJ)

AF:

0.00139

AC:

AN:

23660

East Asian (EAS)

AF:

0.00

AC:

AN:

30934

South Asian (SAS)

AF:

0.000161

AC:

AN:

74680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33632

Middle Eastern (MID)

AF:

0.00456

AC:

AN:

3948

European-Non Finnish (NFE)

AF:

0.000120

AC:

128

AN:

1062740

Other (OTH)

AF:

0.00457

AC:

255

AN:

55822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

142

284

427

569

711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0212

AC:

3231

AN:

152168

Hom.:

Cov.:

AF XY:

0.0204

AC XY:

1519

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0736

AC:

3056

AN:

41510

American (AMR)

AF:

0.00647

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67976

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

164

328

492

656

820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00277

Hom.:

Bravo

AF:

0.0242

Asia WGS

AF:

0.00145

AC:

AN:

3460

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Peroxisome biogenesis disorder (1)

Peroxisome biogenesis disorder 4A (Zellweger) (1)

Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

5.1

(source)

DANN

Benign

0.95

PhyloP100

-1.7

PromoterAI

-0.0053

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over