11-47571510-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_175732.3(PTPMT1):c.487G>A(p.Ala163Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,613,820 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: PTPMT1 NM_175732.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.333

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055808693).
• BP6: Variant 11-47571510-G-A is Benign according to our data. Variant chr11-47571510-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2360508.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPMT1	NM_175732.3	c.487G>A	p.Ala163Thr	missense_variant	4/4	ENST00000326674.10
PTPMT1	NM_001143984.2	c.404G>A	p.Arg135His	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPMT1	ENST00000326674.10	c.487G>A	p.Ala163Thr	missense_variant	4/4	1	NM_175732.3	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000601 AC: 15 AN: 249498 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135372

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: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461856 Hom.: 1 Cov.: 30 AF XY: 0.000188 AC XY: 137 AN XY: 727226

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000220

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151964 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74202

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	8.2
Dann	Uncertain	0.98
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.21	N
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.045
Sift	Benign	0.50	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.059
MVP		0.57
MPC		0.48
ClinPred		0.062	T
GERP RS		0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.15

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: rs201520358; hg19: chr11-47593062; COSMIC: COSV58597186; COSMIC: COSV58597186;