rs879255627

Positions:

• chr5-14397112-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The ENST00000344204.9(TRIO):​c.4381C>A​(p.Pro1461Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1461L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRIO ENST00000344204.9 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.84

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000344204.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-14397113-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 978213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRIO. . Gene score misZ 5.3161 (greater than the threshold 3.09). Trascript score misZ 4.6722 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844
• PP5: Variant 5-14397112-C-A is Pathogenic according to our data. Variant chr5-14397112-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 253085.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-14397112-C-A is described in Lovd as [Pathogenic]. Variant chr5-14397112-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIO	NM_007118.4	c.4381C>A	p.Pro1461Thr	missense_variant	29/57	ENST00000344204.9	NP_009049.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9	c.4381C>A	p.Pro1461Thr	missense_variant	29/57	1	NM_007118.4	ENSP00000339299	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456866 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723828

Gnomad4 AFR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Sep 10, 2020	This variant is interpreted as pathogenic for Intellectual developmental disorder, autosomal dominant 44, with microcephaly. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 31, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.0	D;D;.
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;P;.
Vest4		0.89
MutPred		0.62		Loss of ubiquitination at K1462 (P = 0.1072);.;.;
MVP		0.71
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.89
gMVP		0.77

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: rs879255627; hg19: chr5-14397221;