5-14364638-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Variant links:

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

TRIO links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIO	NM_007118.4 link	c.2588-12T>A		intron_variant	Intron 14 of 56	ENST00000344204.9	NP_009049.2	O75962-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9 link	c.2588-12T>A		intron_variant	Intron 14 of 56	1	NM_007118.4	ENSP00000339299.4		O75962-1

Frequencies

GnomAD3 genomes

AF:

0.00552

AC:

840

AN:

152194

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00822

AC XY:

5936

AN XY:

721976

show subpopulations

African (AFR)

AF:

0.00112

AC:

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

549

1099

1648

2198

2747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

354

708

1062

1416

1770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00550

AC:

837

AN:

152312

Hom.:

Cov.:

AF XY:

0.00552

AC XY:

411

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41568

American (AMR)

AF:

0.00379

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00995

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00518

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00698

AC:

475

AN:

68024

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00818

Hom.:

Bravo

AF:

0.00535

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 27, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.5

(source)

DANN

Benign

0.78

PhyloP100

-0.88

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over