5-14374244-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_007118.4(TRIO):​c.3232C>T​(p.Arg1078Trp) 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 Likely 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 U:1
• Conservation: PhyloP100: 0.300
• Publications: 1 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: Illumina, ClinGen
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 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-T is Pathogenic according to our data. Variant chr5-14374244-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 449111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007118.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	NM_007118.4	MANE Select	c.3232C>T	p.Arg1078Trp	missense	Exon 19 of 57	NP_009049.2
	TRIO	NR_134469.2		n.3616C>T		non_coding_transcript_exon	Exon 19 of 57

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	ENST00000344204.9	TSL:1 MANE Select	c.3232C>T	p.Arg1078Trp	missense	Exon 19 of 57	ENSP00000339299.4	O75962-1
	TRIO	ENST00000515144.5	TSL:1	n.2150C>T		non_coding_transcript_exon	Exon 14 of 43
	TRIO	ENST00000513206.5	TSL:5	c.2431C>T	p.Arg811Trp	missense	Exon 15 of 51	ENSP00000426342.2	E7EPJ7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
4	-	-	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome (4)
3	-	-	Intellectual developmental disorder, autosomal dominant 63, with macrocephaly (3)
1	-	-	Autosomal recessive nonsyndromic hearing loss 28 (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)
1	-	-	Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome;C5394205:Intellectual developmental disorder, autosomal dominant 63, with macrocephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.043
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.39	N
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.30
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.50		Gain of catalytic residue at L1076 (P = 0.0059)
MVP		0.68
MPC		2.0
ClinPred		0.93	D
GERP RS		0.49
Varity_R		0.84
gMVP		0.81
Mutation Taster		=14/86	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: COSV105906500;