12-120446234-A-G

Variant names:

• chr12-120446234-A-G
• NM_016399.3:c.139T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016399.3(TRIAP1):​c.139T>C​(p.Cys47Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRIAP1 NM_016399.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

Genes affected

TRIAP1 (HGNC:26937): (TP53 regulated inhibitor of apoptosis 1) Enables p53 binding activity. Contributes to phosphatidic acid transfer activity. Involved in several processes, including DNA damage response, signal transduction by p53 class mediator; negative regulation of apoptotic process; and positive regulation of phospholipid transport. Located in mitochondrial intermembrane space and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000111780 (HGNC:):

GATC (HGNC:25068): (glutamyl-tRNA amidotransferase subunit C) Enables glutaminyl-tRNA synthase (glutamine-hydrolyzing) activity. Involved in glutaminyl-tRNAGln biosynthesis via transamidation and mitochondrial translation. Located in mitochondrion. Part of glutamyl-tRNA(Gln) amidotransferase complex. Implicated in combined oxidative phosphorylation deficiency 42. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIAP1	NM_016399.3	c.139T>C	p.Cys47Arg	missense_variant	Exon 1 of 2	ENST00000546954.2	NP_057483.1
GATC	NM_176818.3	c.-247A>G		upstream_gene_variant		ENST00000551765.6	NP_789788.1
GATC	NR_033684.2	n.-210A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIAP1	ENST00000546954.2	c.139T>C	p.Cys47Arg	missense_variant	Exon 1 of 2	1	NM_016399.3	ENSP00000449795.1
ENSG00000111780	ENST00000551806.1	c.175-423A>G		intron_variant	Intron 2 of 4	3		ENSP00000450281.1
GATC	ENST00000551765.6	c.-247A>G		upstream_gene_variant		1	NM_176818.3	ENSP00000446872.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139T>C (p.C47R) alteration is located in exon 1 (coding exon 1) of the TRIAP1 gene. This alteration results from a T to C substitution at nucleotide position 139, causing the cysteine (C) at amino acid position 47 to be replaced by an arginine (R). 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	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.33	T
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.85		Gain of MoRF binding (P = 0.0037);
MVP		0.75
MPC		2.0
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr12-120884037;