rs397516554

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001039141.3(TRIOBP):​c.6007G>A​(p.Gly2003Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,556,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 1.23
Variant links:
Genes affected
TRIOBP (HGNC:17009): (TRIO and F-actin binding protein) This gene encodes a protein with an N-terminal pleckstrin homology domain and a C-terminal coiled-coil region. The protein interacts with trio, which is involved with neural tissue development and controlling actin cytoskeleton organization, cell motility and cell growth. The protein also associates with F-actin and stabilizes F-actin structures. Mutations in this gene have been associated with a form of autosomal recessive nonsyndromic deafness. Multiple alternatively spliced transcript variants that would encode different isoforms have been found for this gene, however some transcripts may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Nov 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.034212887).
BP6
Variant 22-37757932-G-A is Benign according to our data. Variant chr22-37757932-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43863.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}. Variant chr22-37757932-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TRIOBPNM_001039141.3 linkuse as main transcriptc.6007G>A p.Gly2003Ser missense_variant 16/24 ENST00000644935.1 NP_001034230.1
TRIOBPNM_007032.5 linkuse as main transcriptc.868G>A p.Gly290Ser missense_variant 6/14 NP_008963.3
TRIOBPNM_138632.2 linkuse as main transcriptc.868G>A p.Gly290Ser missense_variant 6/8 NP_619538.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TRIOBPENST00000644935.1 linkuse as main transcriptc.6007G>A p.Gly2003Ser missense_variant 16/24 NM_001039141.3 ENSP00000496394 A2Q9H2D6-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000652
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000435
AC:
7
AN:
160834
Hom.:
0
AF XY:
0.0000233
AC XY:
2
AN XY:
85846
show subpopulations
Gnomad AFR exome
AF:
0.000472
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000472
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000207
AC:
29
AN:
1403820
Hom.:
0
Cov.:
32
AF XY:
0.0000159
AC XY:
11
AN XY:
693108
show subpopulations
Gnomad4 AFR exome
AF:
0.000252
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000185
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.000650
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.000147
ExAC
AF:
0.0000264
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 10, 2022This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2003 of the TRIOBP protein (p.Gly2003Ser). This variant is present in population databases (rs397516554, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TRIOBP-related conditions. ClinVar contains an entry for this variant (Variation ID: 43863). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 22, 2023The c.6007G>A (p.G2003S) alteration is located in exon 16 (coding exon 14) of the TRIOBP gene. This alteration results from a G to A substitution at nucleotide position 6007, causing the glycine (G) at amino acid position 2003 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJan 29, 2013Gly2003Ser in exon 16 of TRIOBP: This variant is not expected to have clinical significance because glycine (Gly) at position 2003 is not conserved across mamm als and several species, including pika and opposum, carry a serine (Ser) at th is position. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.036
T;T;.;.;.;T;T
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.81
.;T;.;T;T;T;T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.034
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L;L;.;.;.;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.8
N;.;D;D;.;D;D
REVEL
Benign
0.055
Sift
Uncertain
0.012
D;.;T;T;.;D;T
Sift4G
Benign
0.22
T;.;T;T;.;T;T
Polyphen
0.39
B;B;.;.;.;.;.
Vest4
0.23
MVP
0.38
MPC
0.26
ClinPred
0.035
T
GERP RS
3.3
Varity_R
0.11
gMVP
0.36

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397516554; hg19: chr22-38153939; API