5-14445476-T-C

Variant names:

• chr5-14445476-T-C
• rs27114
• NM_007118.4:c.5204-15543T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007118.4(TRIO):​c.5204-15543T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 152,110 control chromosomes in the GnomAD database, including 20,721 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (20721 hom., cov: 32)
• Consequence: TRIO NM_007118.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.41
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

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.5204-15543T>C		intron	N/A	NP_009049.2
	TRIO	NR_134469.2		n.5588-15543T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	ENST00000344204.9	TSL:1 MANE Select	c.5204-15543T>C		intron	N/A	ENSP00000339299.4
	TRIO	ENST00000515144.5	TSL:1	n.4122-15543T>C		intron	N/A
	TRIO	ENST00000513206.5	TSL:5	c.4403-15543T>C		intron	N/A	ENSP00000426342.2

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75488 AN: 151992 Hom.: 20691 Cov.: 32

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.482

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

GnomAD4 genome AF: 0.497 AC: 75577 AN: 152110 Hom.: 20721 Cov.: 32 AF XY: 0.491 AC XY: 36488 AN XY: 74372

African (AFR) AF: 0.736 AC: 30526 AN: 41490

American (AMR) AF: 0.485 AC: 7407 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1980 AN: 3468

East Asian (EAS) AF: 0.192 AC: 992 AN: 5168

South Asian (SAS) AF: 0.418 AC: 2010 AN: 4814

European-Finnish (FIN) AF: 0.317 AC: 3358 AN: 10592

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27696 AN: 67970

Other (OTH) AF: 0.485 AC: 1027 AN: 2116

Alfa AF: 0.434 Hom.: 7910

Bravo AF: 0.515

Asia WGS AF: 0.347 AC: 1211 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.031
DANN	Benign	0.39
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs27114; hg19: chr5-14445585;