chr19-54108382-C-A

Variant names:

• chr19-54108382-C-A
• rs751160649
• NM_013342.4:c.367G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013342.4(TFPT):​c.367G>T​(p.Val123Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFPT NM_013342.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 1 publications found

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]

NDUFA3 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32720178).

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.367G>T	p.Val123Leu	missense	Exon 4 of 6	NP_037474.1	P0C1Z6-1
	TFPT	NM_001321792.2		c.340G>T	p.Val114Leu	missense	Exon 4 of 6	NP_001308721.1	P0C1Z6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFPT	ENST00000391759.6	TSL:1 MANE Select	c.367G>T	p.Val123Leu	missense	Exon 4 of 6	ENSP00000375639.1	P0C1Z6-1
	TFPT	ENST00000391758.5	TSL:1	c.340G>T	p.Val114Leu	missense	Exon 4 of 6	ENSP00000375638.1	P0C1Z6-2
	TFPT	ENST00000911296.1		c.418G>T	p.Val140Leu	missense	Exon 4 of 6	ENSP00000581355.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.0098	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.095
Sift	Benign	0.058	T
Sift4G	Uncertain	0.052	T
Polyphen		0.98	D
Vest4		0.56
MutPred		0.23		Loss of MoRF binding (P = 0.0915)
MVP		0.32
MPC		0.080
ClinPred		0.55	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.41
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs751160649; hg19: chr19-54611689;