Genetic Variant NM_016399.3:c.91G>T (chr12-120446282-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016399.3(TRIAP1):c.91G>T(p.Asp31Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TRIAP1
NM_016399.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53

Variant links:

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]

TRIAP1 links:

ENSG00000111780 (HGNC:):

ENSG00000111780 links:

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]

GATC links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIAP1	NM_016399.3 link	c.91G>T	p.Asp31Tyr	missense_variant	Exon 1 of 2	ENST00000546954.2	NP_057483.1	O43715
GATC	NM_176818.3 link	c.-199C>A		upstream_gene_variant		ENST00000551765.6	NP_789788.1	O43716
GATC	NR_033684.2 link	n.-162C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIAP1	ENST00000546954.2 link	c.91G>T	p.Asp31Tyr	missense_variant	Exon 1 of 2	1	NM_016399.3	ENSP00000449795.1	O43715
ENSG00000111780	ENST00000551806.1 link	c.175-375C>A		intron_variant	Intron 2 of 4	3		ENSP00000450281.1	H0YIV9
GATC	ENST00000551765.6 link	c.-199C>A		upstream_gene_variant		1	NM_176818.3	ENSP00000446872.1	O43716

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251320

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91G>T (p.D31Y) alteration is located in exon 1 (coding exon 1) of the TRIAP1 gene. This alteration results from a G to T substitution at nucleotide position 91, causing the aspartic acid (D) at amino acid position 31 to be replaced by a tyrosine (Y). 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

Uncertain

0.46

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Benign

0.42

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

-0.23

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.35

Sift

Benign

0.053

Sift4G

Uncertain

0.055

Polyphen

0.99

Vest4

0.67

MutPred

0.37

Loss of disorder (P = 0.0349);

MVP

0.25

MPC

1.7

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.82

gMVP

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over