chr5-14374244-C-G

Variant names:

• chr5-14374244-C-G
• rs1554065887
• NM_007118.4:c.3232C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_007118.4(TRIO):​c.3232C>G​(p.Arg1078Gly) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1078Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRIO NM_007118.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.300
• Publications: 0 publications found

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]

TRIO Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• intellectual developmental disorder, autosomal dominant 63, with macrocephaly

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_007118.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-14374245-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 830227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 5-14374244-C-G is Pathogenic according to our data. Variant chr5-14374244-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 830226.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIO	NM_007118.4	c.3232C>G	p.Arg1078Gly	missense_variant	Exon 19 of 57	ENST00000344204.9	NP_009049.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9	c.3232C>G	p.Arg1078Gly	missense_variant	Exon 19 of 57	1	NM_007118.4	ENSP00000339299.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder, autosomal dominant 63, with macrocephaly Pathogenic:2

Sep 10, 2020

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as pathogenic for Intellectual developmental disorder, autosomal dominant 63, with macrocephaly. 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); Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5); Well-established functional studies show a deleterious effect (PS3 downgraded to moderate). -

Mar 31, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;T;T
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.43	N
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.4	M;.;.
PhyloP100		0.30
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.3	D;D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.87
MutPred		0.54		Loss of MoRF binding (P = 0.0324);.;.;
MVP		0.62
MPC		2.2
ClinPred		1.0	D
GERP RS		0.49
Varity_R		0.89
gMVP		0.83
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554065887; hg19: chr5-14374353; COSMIC: COSV60087614;