19-54108382-C-T

Variant names:

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

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>A​(p.Val123Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V123L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• 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=0.40831354).

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>A	p.Val123Met	missense	Exon 4 of 6	NP_037474.1	P0C1Z6-1
	TFPT	NM_001321792.2		c.340G>A	p.Val114Met	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>A	p.Val123Met	missense	Exon 4 of 6	ENSP00000375639.1	P0C1Z6-1
	TFPT	ENST00000391758.5	TSL:1	c.340G>A	p.Val114Met	missense	Exon 4 of 6	ENSP00000375638.1	P0C1Z6-2
	TFPT	ENST00000911296.1		c.418G>A	p.Val140Met	missense	Exon 4 of 6	ENSP00000581355.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249982 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461314 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 726840

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111724

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.15
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.25		Gain of disorder (P = 0.0437)
MVP		0.33
MPC		0.38
ClinPred		0.70	D
GERP RS		4.6
Varity_R		0.13
gMVP		0.39
Mutation Taster		=85/15	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;