5-14143759-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.34G>A(p.Ala12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 993,654 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A12S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TRIO NM_007118.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.18

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=0.056898147).
• BP6: Variant 5-14143759-G-A is Benign according to our data. Variant chr5-14143759-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 785114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-14143759-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00129 (188/146150) while in subpopulation AFR AF= 0.00409 (167/40842). AF 95% confidence interval is 0.00358. There are 0 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIO	NM_007118.4	c.34G>A	p.Ala12Thr	missense_variant	1/57	ENST00000344204.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIO	ENST00000344204.9	c.34G>A	p.Ala12Thr	missense_variant	1/57	1	NM_007118.4	P1
TRIO	ENST00000698541.1	c.34G>A	p.Ala12Thr	missense_variant	1/37
TRIO	ENST00000502816.1	n.58G>A		non_coding_transcript_exon_variant	1/5	2
TRIO	ENST00000505971.5	n.58G>A		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 186 AN: 146086 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00645

Gnomad NFE AF: 0.0000760

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000181 AC: 153 AN: 847504 Hom.: 0 Cov.: 29 AF XY: 0.000181 AC XY: 71 AN XY: 392810

Gnomad4 AFR exome AF: 0.00560

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: 0.0000583

Gnomad4 OTH exome AF: 0.000567

GnomAD4 genome AF: 0.00129 AC: 188 AN: 146150 Hom.: 0 Cov.: 31 AF XY: 0.00148 AC XY: 105 AN XY: 71090

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.000948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000761

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000925 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	TRIO: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2020	- -

TRIO-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 16, 2024

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

Apr 03, 2021

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	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.15		Gain of glycosylation at A12 (P = 0.0011);
MVP		0.34
MPC		0.81
ClinPred		0.16	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.16

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: rs1045136451; hg19: chr5-14143868;