5-14143792-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007118.4(TRIO):c.67G>A(p.Ala23Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,037,030 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TRIO NM_007118.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0470

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRIO
• BP4: Computational evidence support a benign effect (MetaRNN=0.01873082).
• BP6: Variant 5-14143792-G-A is Benign according to our data. Variant chr5-14143792-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 714992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00107 (157/147030) while in subpopulation AFR AF= 0.00349 (143/41006). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 155 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIO	NM_007118.4	c.67G>A	p.Ala23Thr	missense_variant	1/57	ENST00000344204.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIO	ENST00000344204.9	c.67G>A	p.Ala23Thr	missense_variant	1/57	1	NM_007118.4	P1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 155 AN: 146944 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000473

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.0000454

Gnomad OTH AF: 0.000983

GnomAD4 exome AF: 0.000138 AC: 123 AN: 890000 Hom.: 0 Cov.: 30 AF XY: 0.000147 AC XY: 61 AN XY: 415458

Gnomad4 AFR exome AF: 0.00362

Gnomad4 AMR exome AF: 0.000381

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: 0.0000663

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.00107 AC: 157 AN: 147030 Hom.: 0 Cov.: 31 AF XY: 0.00119 AC XY: 85 AN XY: 71632

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.000472

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000454

Gnomad4 OTH AF: 0.000974

Alfa AF: 0.000139 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 16, 2018	- -

TRIO-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.20	N
REVEL	Benign	0.11
Sift	Benign	0.066	T
Sift4G	Uncertain	0.029	D
Polyphen		0.0010	B
Vest4		0.10
MVP		0.43
MPC		0.88
ClinPred		0.17	T
GERP RS		0.19
Varity_R		0.080
gMVP		0.25

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

Other links and lift over

dbSNP: rs566570633; hg19: chr5-14143901;