rs55900671

chr5-14508238-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRIO
• 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 380 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIO	NM_007118.4	c.9110A>T	p.Lys3037Met	missense_variant	57/57	ENST00000344204.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIO	ENST00000344204.9	c.9110A>T	p.Lys3037Met	missense_variant	57/57	1	NM_007118.4	P1

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152206 Hom.: 10 Cov.: 33

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

GnomAD3 exomes AF: 0.00443 AC: 1114 AN: 251326 Hom.: 28 AF XY: 0.00440 AC XY: 598 AN XY: 135860

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 SAS exome AF: 0.00301

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.: 58 Cov.: 31 AF XY: 0.00200 AC XY: 1451 AN XY: 727182

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0496

Gnomad4 SAS exome AF: 0.00330

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.00251 AC: 383 AN: 152324 Hom.: 10 Cov.: 33 AF XY: 0.00289 AC XY: 215 AN XY: 74488

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0504

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00217 Hom.: 11

Bravo AF: 0.00239

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00409 AC: 497

Asia WGS AF: 0.0250 AC: 85 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.1	N;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.33
MVP		0.53
MPC		0.40
ClinPred		0.014	T
GERP RS		1.9
Varity_R		0.27
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs55900671; hg19: chr5-14508347; COSMIC: COSV59988639; COSMIC: COSV59988639;