rs146739260

Variant names:

• chr5-14364638-T-A
• rs146739260
• NM_007118.4:c.2588-12T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007118.4(TRIO):​c.2588-12T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00775 in 1,604,768 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (84 hom.)
• Consequence: TRIO NM_007118.4 intron
• Scores: Splicing: ADA: 0.07208
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.878
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-14364638-T-A is Benign according to our data. Variant chr5-14364638-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0055 (837/152312) while in subpopulation SAS AF = 0.00995 (48/4826). AF 95% confidence interval is 0.00771. There are 8 homozygotes in GnomAd4. There are 411 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 837 AD gene.

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.2588-12T>A		intron	N/A	NP_009049.2
	TRIO	NR_134469.2		n.2972-12T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	ENST00000344204.9	TSL:1 MANE Select	c.2588-12T>A		intron	N/A	ENSP00000339299.4	O75962-1
	TRIO	ENST00000515144.5	TSL:1	n.1506-12T>A		intron	N/A
	TRIO	ENST00000513206.5	TSL:5	c.1787-12T>A		intron	N/A	ENSP00000426342.2	E7EPJ7

Frequencies

GnomAD3 genomes AF: 0.00552 AC: 840 AN: 152194 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00698

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00728 AC: 1776 AN: 243946 AF XY: 0.00817

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.00537

Gnomad NFE exome AF: 0.00731

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.00798 AC: 11595 AN: 1452456 Hom.: 84 Cov.: 31 AF XY: 0.00822 AC XY: 5936 AN XY: 721976

African (AFR) AF: 0.00112 AC: 37 AN: 32934

American (AMR) AF: 0.00250 AC: 108 AN: 43194

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 638 AN: 25576

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39450

South Asian (SAS) AF: 0.0164 AC: 1398 AN: 85092

European-Finnish (FIN) AF: 0.00452 AC: 241 AN: 53272

Middle Eastern (MID) AF: 0.0263 AC: 150 AN: 5700

European-Non Finnish (NFE) AF: 0.00767 AC: 8495 AN: 1107324

Other (OTH) AF: 0.00876 AC: 525 AN: 59914

GnomAD4 genome AF: 0.00550 AC: 837 AN: 152312 Hom.: 8 Cov.: 33 AF XY: 0.00552 AC XY: 411 AN XY: 74496

African (AFR) AF: 0.00156 AC: 65 AN: 41568

American (AMR) AF: 0.00379 AC: 58 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00995 AC: 48 AN: 4826

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00698 AC: 475 AN: 68024

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.00818 Hom.: 1

Bravo AF: 0.00535

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.5
DANN	Benign	0.78
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.072
dbscSNV1_RF	Benign	0.25
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: rs146739260; hg19: chr5-14364747;