11-47571585-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175732.3(PTPMT1):c.562G>A(p.Ala188Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPMT1 NM_175732.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.531

Genes affected

PTPMT1 (HGNC:26965): (protein tyrosine phosphatase mitochondrial 1) Predicted to enable phosphatidylglycerophosphatase activity and phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity. Involved in regulation of intrinsic apoptotic signaling pathway. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

NDUFS3 (HGNC:7710): (NADH:ubiquinone oxidoreductase core subunit S3) This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.[provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0687069).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPMT1	NM_175732.3	c.562G>A	p.Ala188Thr	missense_variant	4/4	ENST00000326674.10
PTPMT1	NM_001143984.2	c.*23G>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPMT1	ENST00000326674.10	c.562G>A	p.Ala188Thr	missense_variant	4/4	1	NM_175732.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249534 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.562G>A (p.A188T) alteration is located in exon 4 (coding exon 4) of the PTPMT1 gene. This alteration results from a G to A substitution at nucleotide position 562, causing the alanine (A) at amino acid position 188 to be replaced by a threonine (T). 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	0.074
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	8.6
Dann	Benign	0.95
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.072
Sift	Benign	0.15	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0010	B;B
Vest4		0.14
MutPred		0.48		.;Gain of glycosylation at A188 (P = 0.0483);
MVP		0.25
MPC		0.47
ClinPred		0.023	T
GERP RS		1.5
Varity_R		0.027
gMVP		0.16

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: rs769003485; hg19: chr11-47593137;