rs1554083396

Variant names:

• chr5-14462845-G-C
• rs1554083396
• NM_007118.4:c.5587G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007118.4(TRIO):​c.5587G>C​(p.Gly1863Arg) variant causes a missense change involving the alteration of a 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: 33)
• Consequence: TRIO NM_007118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	NM_007118.4	MANE Select	c.5587G>C	p.Gly1863Arg	missense	Exon 36 of 57	NP_009049.2
	TRIO	NR_134469.2		n.5971G>C		non_coding_transcript_exon	Exon 36 of 57

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	ENST00000344204.9	TSL:1 MANE Select	c.5587G>C	p.Gly1863Arg	missense	Exon 36 of 57	ENSP00000339299.4
	TRIO	ENST00000515144.5	TSL:1	n.4505G>C		non_coding_transcript_exon	Exon 31 of 43
	TRIO	ENST00000513206.5	TSL:5	c.4786G>C	p.Gly1596Arg	missense	Exon 32 of 51	ENSP00000426342.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.28
Sift	Benign	0.057	T
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.31		Gain of solvent accessibility (P = 0.0263)
MVP		0.46
MPC		1.0
ClinPred		0.70	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.25
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554083396; hg19: chr5-14462954;