11-47571539-G-T

Variant names:

• chr11-47571539-G-T
• rs780466841
• NM_175732.3:c.516G>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_175732.3(PTPMT1):​c.516G>T​(p.Arg172Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,846 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (1 hom.)
• Consequence: PTPMT1 NM_175732.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.105

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057259917).
• BS2: High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPMT1	NM_175732.3	c.516G>T	p.Arg172Ser	missense_variant	Exon 4 of 4	ENST00000326674.10	NP_783859.1
PTPMT1	NM_001143984.2	c.433G>T	p.Ala145Ser	missense_variant	Exon 2 of 2		NP_001137456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPMT1	ENST00000326674.10	c.516G>T	p.Arg172Ser	missense_variant	Exon 4 of 4	1	NM_175732.3	ENSP00000325958.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000561 AC: 14 AN: 249536 Hom.: 0 AF XY: 0.0000813 AC XY: 11 AN XY: 135376

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: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461846 Hom.: 1 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 727222

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: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000745 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.516G>T (p.R172S) alteration is located in exon 4 (coding exon 4) of the PTPMT1 gene. This alteration results from a G to T substitution at nucleotide position 516, causing the arginine (R) at amino acid position 172 to be replaced by a serine (S). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.82
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.81	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.017
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.083	T
Vest4		0.15
MutPred		0.29		Loss of catalytic residue at A145 (P = 0.003);
MVP		0.41
ClinPred		0.81	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs780466841; hg19: chr11-47593091;