5-14143748-C-G

Variant names:

• chr5-14143748-C-G
• NM_007118.4:c.23C>G

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.23C>G​(p.Ala8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRIO NM_007118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.610

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 in the TRIO gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 80 curated benign missense variants. Gene score misZ: 5.3161 (above the threshold of 3.09). Trascript score misZ: 4.6722 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, syndromic intellectual disability, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20921251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIO	NM_007118.4	c.23C>G	p.Ala8Gly	missense_variant	Exon 1 of 57	ENST00000344204.9	NP_009049.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9	c.23C>G	p.Ala8Gly	missense_variant	Exon 1 of 57	1	NM_007118.4	ENSP00000339299.4
TRIO	ENST00000698541.1	c.23C>G	p.Ala8Gly	missense_variant	Exon 1 of 37			ENSP00000513786.1
TRIO	ENST00000502816.1	n.47C>G		non_coding_transcript_exon_variant	Exon 1 of 5	2
TRIO	ENST00000505971.5	n.47C>G		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

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

Nov 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23C>G (p.A8G) alteration is located in exon 1 (coding exon 1) of the TRIO gene. This alteration results from a C to G substitution at nucleotide position 23, causing the alanine (A) at amino acid position 8 to be replaced by a glycine (G). 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	0.072
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.33	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.074	T
Polyphen		0.64	P
Vest4		0.16
MutPred		0.15		Gain of loop (P = 0.0435);
MVP		0.43
MPC		0.84
ClinPred		0.28	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.10

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: chr5-14143857;