Genetic Variant NM_001039141.3:c.4703C>T (chr22-37735039-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001039141.3(TRIOBP):c.4703C>T(p.Ala1568Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1568G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.05

Publications

0 publications found

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]

TRIOBP Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 28
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

TRIOBP links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051265508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.4703C>T	p.Ala1568Val	missense_variant	Exon 9 of 24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIOBP	ENST00000644935.1 link	c.4703C>T	p.Ala1568Val	missense_variant	Exon 9 of 24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
TRIOBP	ENST00000344404.10 link	n.*4186C>T		non_coding_transcript_exon_variant	Exon 7 of 22	2		ENSP00000340312.6	H7BXW4
TRIOBP	ENST00000344404.10 link	n.*4186C>T		3_prime_UTR_variant	Exon 7 of 22	2		ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456218

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39574

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108222

Other (OTH)

AF:

0.00

AC:

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.86

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.043

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.45

.;T

M_CAP

Benign

0.0084

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;L

PhyloP100

-1.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.039

Sift

Benign

0.12

T;.

Sift4G

Benign

0.098

T;.

Polyphen

0.0050

B;B

Vest4

0.050

MutPred

0.13

Loss of disorder (P = 0.0881);Loss of disorder (P = 0.0881);

MVP

0.15

MPC

0.12

ClinPred

0.076

GERP RS

-7.1

Varity_R

0.029

gMVP

0.044

Mutation Taster

=97/3

polymorphism

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over