chr19-54108357-T-G

Position:

• chr19-54108357-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013342.4(TFPT):​c.392A>C​(p.Tyr131Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.0000014 (0 hom.)
• Consequence: TFPT NM_013342.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFPT	NM_013342.4	c.392A>C	p.Tyr131Ser	missense_variant	4/6	ENST00000391759.6	NP_037474.1
TFPT	NM_001321792.2	c.365A>C	p.Tyr122Ser	missense_variant	4/6		NP_001308721.1
TFPT	XM_005278261.2	c.32A>C	p.Tyr11Ser	missense_variant	3/5		XP_005278318.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFPT	ENST00000391759.6	c.392A>C	p.Tyr131Ser	missense_variant	4/6	1	NM_013342.4	ENSP00000375639.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458516 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725308

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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, 2024

The c.392A>C (p.Y131S) alteration is located in exon 4 (coding exon 4) of the TFPT gene. This alteration results from a A to C substitution at nucleotide position 392, causing the tyrosine (Y) at amino acid position 131 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	D;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.86
MutPred		0.65		Gain of disorder (P = 0.0068);.;Gain of disorder (P = 0.0068);
MVP		0.38
MPC		0.49
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.81
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54611664;