rs55900671

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.9110A>T(p.Lys3037Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,058 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 58 hom. )

Consequence

TRIO
NM_007118.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.98

Publications

6 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 (MetaRNN=0.01017791).

BP6

Variant 5-14508238-A-T is Benign according to our data. Variant chr5-14508238-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00251 (383/152324) while in subpopulation EAS AF = 0.0504 (261/5176). AF 95% confidence interval is 0.0454. There are 10 homozygotes in GnomAd4. There are 215 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 383 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.9110A>T	p.Lys3037Met	missense	Exon 57 of 57	NP_009049.2
	TRIO	NR_134469.2		n.8964A>T		non_coding_transcript_exon	Exon 57 of 57

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRIO	ENST00000344204.9	TSL:1 MANE Select	c.9110A>T	p.Lys3037Met	missense	Exon 57 of 57	ENSP00000339299.4
TRIO	ENST00000513206.5	TSL:5	c.7610+5581A>T		intron	N/A	ENSP00000426342.2
TRIO	ENST00000344135.5	TSL:2	n.2100A>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0505

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00443

AC:

1114

AN:

251326

AF XY:

0.00440

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0495

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00191

AC:

2786

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1451

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33480

American (AMR)

AF:

0.000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0496

AC:

1970

AN:

39700

South Asian (SAS)

AF:

0.00330

AC:

285

AN:

86258

European-Finnish (FIN)

AF:

0.00131

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000165

AC:

184

AN:

1112012

Other (OTH)

AF:

0.00382

AC:

231

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

201

401

602

802

1003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.00251

AC:

383

AN:

152324

Hom.:

Cov.:

AF XY:

0.00289

AC XY:

215

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41580

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0504

AC:

261

AN:

5176

South Asian (SAS)

AF:

0.00498

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68024

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00217

Hom.:

Bravo

AF:

0.00239

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00409

AC:

497

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.2

PhyloP100

2.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.36

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.33

MVP

0.53

MPC

0.40

ClinPred

0.014

GERP RS

1.9

Varity_R

0.27

gMVP

0.58

Mutation Taster

=90/10

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over