7-99423814-C-A

Variant names:

• chr7-99423814-C-A
• rs1562839524
• NM_015545.4:c.1881G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015545.4(PTCD1):​c.1881G>T​(p.Gln627His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTCD1 NM_015545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCD1	NM_015545.4	c.1881G>T	p.Gln627His	missense_variant	Exon 7 of 8	ENST00000292478.9	NP_056360.2
ATP5MF-PTCD1	NM_001198879.2	c.2028G>T	p.Gln676His	missense_variant	Exon 8 of 9		NP_001185808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCD1	ENST00000292478.9	c.1881G>T	p.Gln627His	missense_variant	Exon 7 of 8	1	NM_015545.4	ENSP00000292478.5
ATP5MF-PTCD1	ENST00000413834.5	c.2028G>T	p.Gln676His	missense_variant	Exon 8 of 9	2		ENSP00000400168.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251472 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2028G>T (p.Q676H) alteration is located in exon 8 (coding exon 8) of the ATP5J2-PTCD1 gene. This alteration results from a G to T substitution at nucleotide position 2028, causing the glutamine (Q) at amino acid position 676 to be replaced by a histidine (H). 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	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;.
Eigen	Benign	0.087
Eigen_PC	Benign	0.049
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.44
Sift	Benign	0.16	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.43		.;Gain of catalytic residue at I674 (P = 0.2755);
MVP		0.64
MPC		0.49
ClinPred		0.93	D
GERP RS		0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1562839524; hg19: chr7-99021437;