5-14143747-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_007118.4(TRIO):c.22G>A(p.Ala8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000239 in 838,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: TRIO NM_007118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.432

Genes affected

TRIO (HGNC:12303): (trio Rho guanine nucleotide exchange factor) This gene encodes a large protein that functions as a GDP to GTP exchange factor. This protein promotes the reorganization of the actin cytoskeleton, thereby playing a role in cell migration and growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRIO
• BP4: Computational evidence support a benign effect (MetaRNN=0.21700001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIO	NM_007118.4	c.22G>A	p.Ala8Thr	missense_variant	1/57	ENST00000344204.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIO	ENST00000344204.9	c.22G>A	p.Ala8Thr	missense_variant	1/57	1	NM_007118.4	P1
TRIO	ENST00000698541.1	c.22G>A	p.Ala8Thr	missense_variant	1/37
TRIO	ENST00000502816.1	n.46G>A		non_coding_transcript_exon_variant	1/5	2
TRIO	ENST00000505971.5	n.46G>A		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000239 AC: 2 AN: 838038 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 387652

Gnomad4 AFR exome AF: 0.0000631

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000362

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The c.22G>A (p.A8T) alteration is located in exon 1 (coding exon 1) of the TRIO gene. This alteration results from a G to A substitution at nucleotide position 22, causing the alanine (A) at amino acid position 8 to be replaced by a threonine (T). 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	Benign	0.14
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.044	D
Polyphen		0.81	P
Vest4		0.16
MutPred		0.14		Gain of glycosylation at A8 (P = 0.0019);
MVP		0.45
MPC		0.81
ClinPred		0.29	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-14143856;