Genetic Variant TFPT:p.Arg200Leu (chr19-54108069-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013342.4(TFPT):c.599G>T(p.Arg200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TFPT
NM_013342.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

Publications

0 publications found

Variant links:

Genes affected

TFPT (HGNC:13630): (TCF3 fusion partner) Predicted to enable DNA binding activity and protein kinase binding activity. Involved in apoptotic signaling pathway. Located in nucleoplasm. Part of Ino80 complex. [provided by Alliance of Genome Resources, Apr 2022]

TFPT links:

NDUFA3 (HGNC:7686): (NADH:ubiquinone oxidoreductase subunit A3) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Part of mitochondrial respiratory chain complex I. [provided by Alliance of Genome Resources, Apr 2022]

NDUFA3 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

NDUFA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.113045305).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013342.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPT	NM_013342.4	MANE Select	c.599G>T	p.Arg200Leu	missense	Exon 5 of 6	NP_037474.1	P0C1Z6-1
	TFPT	NM_001321792.2		c.572G>T	p.Arg191Leu	missense	Exon 5 of 6	NP_001308721.1	P0C1Z6-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFPT	ENST00000391759.6	TSL:1 MANE Select	c.599G>T	p.Arg200Leu	missense	Exon 5 of 6	ENSP00000375639.1	P0C1Z6-1
TFPT	ENST00000391758.5	TSL:1	c.572G>T	p.Arg191Leu	missense	Exon 5 of 6	ENSP00000375638.1	P0C1Z6-2
TFPT	ENST00000911296.1		c.650G>T	p.Arg217Leu	missense	Exon 5 of 6	ENSP00000581355.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1392802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686136

African (AFR)

AF:

0.00

AC:

AN:

31036

American (AMR)

AF:

0.00

AC:

AN:

33790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21182

East Asian (EAS)

AF:

0.00

AC:

AN:

39106

South Asian (SAS)

AF:

0.00

AC:

AN:

75712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50748

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5406

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078596

Other (OTH)

AF:

0.00

AC:

AN:

57226

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.24

M_CAP

Benign

0.016

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PhyloP100

1.6

PROVEAN

Benign

0.18

REVEL

Benign

0.061

Sift

Pathogenic

0.0

Vest4

0.29

MutPred

0.17

Gain of phosphorylation at A188 (P = 0.0276)

MVP

0.40

ClinPred

0.58

GERP RS

4.7

Varity_R

0.16

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over