5-14143780-GC-TT

Variant names:

• chr5-14143780-GC-TT
• NM_007118.4:c.55_56delGCinsTT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_007118.4(TRIO):​c.55_56delGCinsTT​(p.Ala19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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:2
• Conservation: PhyloP100: 2.76

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIO	NM_007118.4	c.55_56delGCinsTT	p.Ala19Leu	missense_variant		ENST00000344204.9	NP_009049.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9	c.55_56delGCinsTT	p.Ala19Leu	missense_variant		1	NM_007118.4	ENSP00000339299.4
TRIO	ENST00000698541.1	c.55_56delGCinsTT	p.Ala19Leu	missense_variant				ENSP00000513786.1
TRIO	ENST00000502816.1	n.79_80delGCinsTT		non_coding_transcript_exon_variant	Exon 1 of 5	2
TRIO	ENST00000505971.5	n.79_80delGCinsTT		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

TRIO-related disorder Uncertain:1

May 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TRIO c.55_56delinsTT variant is predicted to result in an in-frame deletion and insertion. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Apr 25, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr5-14143889;