7-99424901-G-A

Variant names:

• chr7-99424901-G-A
• rs780978634
• NM_015545.4:c.1631C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015545.4(PTCD1):​c.1631C>T​(p.Pro544Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000508 in 1,614,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: PTCD1 NM_015545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36815804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCD1	NM_015545.4	c.1631C>T	p.Pro544Leu	missense_variant	Exon 6 of 8	ENST00000292478.9	NP_056360.2
ATP5MF-PTCD1	NM_001198879.2	c.1778C>T	p.Pro593Leu	missense_variant	Exon 7 of 9		NP_001185808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCD1	ENST00000292478.9	c.1631C>T	p.Pro544Leu	missense_variant	Exon 6 of 8	1	NM_015545.4	ENSP00000292478.5
ATP5MF-PTCD1	ENST00000413834.5	c.1778C>T	p.Pro593Leu	missense_variant	Exon 7 of 9	2		ENSP00000400168.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152234 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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251414 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135900

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000540

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74502

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: 0.0000941

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000711 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1778C>T (p.P593L) alteration is located in exon 7 (coding exon 7) of the ATP5J2-PTCD1 gene. This alteration results from a C to T substitution at nucleotide position 1778, causing the proline (P) at amino acid position 593 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.071	T;T
Polyphen		0.95	P;P
Vest4		0.38
MVP		0.79
MPC		0.22
ClinPred		0.21	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.70

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: rs780978634; hg19: chr7-99022524;