rs150504114

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015545.4(PTCD1):c.307C>T(p.Arg103Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,614,224 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R103H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0087 ( 9 hom., cov: 32)

Exomes 𝑓: 0.012 ( 120 hom. )

Consequence

PTCD1
NM_015545.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.69

Publications

11 publications found

Variant links:

Genes affected

PTCD1 (HGNC:22198): (pentatricopeptide repeat domain 1) This gene encodes a mitochondrial protein that binds leucine tRNAs and other mitochondrial RNAs and plays a role in the regulation of translation. Increased expression of this gene results in decreased mitochondrial leucine tRNA levels. Naturally occurring read-through transcription exists between upstream ATP5J2 (ATP synthase, H+ transporting, mitochondrial Fo complex, subunit F2) and this gene. [provided by RefSeq, Aug 2015]

PTCD1 links:

ATP5MF-PTCD1 (HGNC:38844): (ATP5MF-PTCD1 readthrough) This locus represents naturally occurring read-through transcription between the ATP5J2 (ATP synthase, H+ transporting, mitochondrial Fo complex, subunit F2) and PTCD1 (pentatricopeptide repeat domain 1) genes on chromosome 7. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Nov 2010]

ATP5MF-PTCD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010560513).

BP6

Variant 7-99434936-G-A is Benign according to our data. Variant chr7-99434936-G-A is described in ClinVar as Benign. ClinVar VariationId is 424616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00874 (1331/152330) while in subpopulation AMR AF = 0.0175 (268/15294). AF 95% confidence interval is 0.0158. There are 9 homozygotes in GnomAd4. There are 611 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCD1	NM_015545.4 link	c.307C>T	p.Arg103Cys	missense_variant	Exon 2 of 8	ENST00000292478.9	NP_056360.2	O75127A4D273
ATP5MF-PTCD1	NM_001198879.2 link	c.454C>T	p.Arg152Cys	missense_variant	Exon 3 of 9		NP_001185808.1	G3V325B4DJ38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCD1	ENST00000292478.9 link	c.307C>T	p.Arg103Cys	missense_variant	Exon 2 of 8	1	NM_015545.4	ENSP00000292478.5		O75127
ATP5MF-PTCD1	ENST00000413834.5 link	c.454C>T	p.Arg152Cys	missense_variant	Exon 3 of 9	2		ENSP00000400168.1		G3V325

Frequencies

GnomAD3 genomes

AF:

0.00874

AC:

1331

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0175

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.00956

AC:

2405

AN:

251494

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.0154

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0116

AC:

17020

AN:

1461894

Hom.:

120

Cov.:

AF XY:

0.0118

AC XY:

8574

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00266

AC:

AN:

33480

American (AMR)

AF:

0.0141

AC:

631

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

460

AN:

26136

East Asian (EAS)

AF:

0.000831

AC:

AN:

39700

South Asian (SAS)

AF:

0.00974

AC:

840

AN:

86258

European-Finnish (FIN)

AF:

0.000655

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0132

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0127

AC:

14118

AN:

1112012

Other (OTH)

AF:

0.0122

AC:

738

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1340

2680

4021

5361

6701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.00874

AC:

1331

AN:

152330

Hom.:

Cov.:

AF XY:

0.00820

AC XY:

611

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00257

AC:

107

AN:

41576

American (AMR)

AF:

0.0175

AC:

268

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.00849

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

808

AN:

68030

Other (OTH)

AF:

0.0142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

144

216

288

360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0109

Hom.:

Bravo

AF:

0.00970

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0141

AC:

121

ExAC

AF:

0.00927

AC:

1126

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Kabuki syndrome 1

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Arg103Cys variant, sometimes called p.Arg152Cys due to a difference in cDNA numbering, in PTCD1 has been identified in an individual with Complex I deficiency (PMID: 20818383), and has been identified in >1% of European (non-Finnish) chromosomes and 13 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Complex I deficiency. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

T;.;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.68

T;T;T;T;T

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Uncertain

0.0085

MutationAssessor

Benign

2.0

M;.;.;.;.

PhyloP100

5.7

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0040

D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;.;D;D

Polyphen

1.0

D;.;.;.;D

Vest4

0.28

MVP

0.97

MPC

0.43

ClinPred

0.025

GERP RS

6.0

Varity_R

0.092

gMVP

0.26

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over