chr19-54108069-C-T

Variant names:

• chr19-54108069-C-T
• rs751744667
• NM_013342.4:c.599G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013342.4(TFPT):​c.599G>A​(p.Arg200His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 1,392,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TFPT NM_013342.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08215508).

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>A	p.Arg200His	missense	Exon 5 of 6	NP_037474.1	P0C1Z6-1
	TFPT	NM_001321792.2		c.572G>A	p.Arg191His	missense	Exon 5 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.599G>A	p.Arg200His	missense	Exon 5 of 6	ENSP00000375639.1	P0C1Z6-1
	TFPT	ENST00000391758.5	TSL:1	c.572G>A	p.Arg191His	missense	Exon 5 of 6	ENSP00000375638.1	P0C1Z6-2
	TFPT	ENST00000911296.1		c.650G>A	p.Arg217His	missense	Exon 5 of 6	ENSP00000581355.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000714 AC: 14 AN: 196140 AF XY: 0.0000575

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000800

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000182

Gnomad FIN exome AF: 0.0000553

Gnomad NFE exome AF: 0.0000763

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000460 AC: 64 AN: 1392802 Hom.: 0 Cov.: 33 AF XY: 0.0000408 AC XY: 28 AN XY: 686136

African (AFR) AF: 0.00 AC: 0 AN: 31036

American (AMR) AF: 0.0000296 AC: 1 AN: 33790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21182

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39106

South Asian (SAS) AF: 0.0000264 AC: 2 AN: 75712

European-Finnish (FIN) AF: 0.0000197 AC: 1 AN: 50748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5406

European-Non Finnish (NFE) AF: 0.0000510 AC: 55 AN: 1078596

Other (OTH) AF: 0.0000175 AC: 1 AN: 57226

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000197 AC: 3 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000496 AC: 6

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.070
Sift	Pathogenic	0.0	D
Vest4		0.23
MutPred		0.14		Gain of loop (P = 0.0435)
MVP		0.40
ClinPred		0.051	T
GERP RS		4.7
Varity_R		0.075
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751744667; hg19: chr19-54611376;