Genetic Variant TFPT:p.Phe223Ser (chr19-54107144-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_013342.4(TFPT):c.668T>C(p.Phe223Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

TFPT
NM_013342.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.69

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2657948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFPT	NM_013342.4 link	c.668T>C	p.Phe223Ser	missense_variant	Exon 6 of 6	ENST00000391759.6	NP_037474.1	P0C1Z6-1A0A024R4Q5
NDUFA3	NM_004542.4 link	c.*242A>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000485876.6	NP_004533.1	O95167Q6FGG4
TFPT	NM_001321792.2 link	c.641T>C	p.Phe214Ser	missense_variant	Exon 6 of 6		NP_001308721.1	P0C1Z6-2
TFPT	XM_005278261.2 link	c.308T>C	p.Phe103Ser	missense_variant	Exon 5 of 5		XP_005278318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFPT	ENST00000391759.6 link	c.668T>C	p.Phe223Ser	missense_variant	Exon 6 of 6	1	NM_013342.4	ENSP00000375639.1		P0C1Z6-1
NDUFA3	ENST00000485876.6 link	c.*242A>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_004542.4	ENSP00000418438.1		O95167

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251356

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000738

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:

0.00000958

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000987

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000347

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668T>C (p.F223S) alteration is located in exon 6 (coding exon 6) of the TFPT gene. This alteration results from a T to C substitution at nucleotide position 668, causing the phenylalanine (F) at amino acid position 223 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

0.53

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.049

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.46

N;.

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

0.19

N;N

REVEL

Benign

0.19

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.059

T;T

Polyphen

0.0010

B;.

Vest4

0.70

MVP

0.44

MPC

0.12

ClinPred

0.078

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over