Genetic Variant NM_001039141.3:c.5167C>G (chr22-37738702-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039141.3(TRIOBP):c.5167C>G(p.Gln1723Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,758 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. Q1723K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

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:

LOC124905115 (HGNC:):

LOC124905115 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08545208).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3 link	c.5167C>G	p.Gln1723Glu	missense_variant	Exon 10 of 24	ENST00000644935.1	NP_001034230.1	Q9H2D6-1
LOC124905115	XM_047441691.1 link	c.*843G>C		3_prime_UTR_variant	Exon 3 of 3		XP_047297647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIOBP	ENST00000644935.1 link	c.5167C>G	p.Gln1723Glu	missense_variant	Exon 10 of 24		NM_001039141.3	ENSP00000496394.1	Q9H2D6-1
TRIOBP	ENST00000344404.10 link	n.*4650C>G		non_coding_transcript_exon_variant	Exon 8 of 22	2		ENSP00000340312.6	H7BXW4
TRIOBP	ENST00000344404.10 link	n.*4650C>G		3_prime_UTR_variant	Exon 8 of 22	2		ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111950

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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

0.075

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.027

T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.49

.;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.085

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

PhyloP100

1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.56

N;.

REVEL

Benign

0.081

Sift

Benign

0.087

T;.

Sift4G

Benign

0.51

T;.

Polyphen

0.0020

B;B

Vest4

0.12

MutPred

0.061

Loss of methylation at K1724 (P = 0.2011);Loss of methylation at K1724 (P = 0.2011);

MVP

0.30

MPC

0.13

ClinPred

0.11

GERP RS

2.5

Varity_R

0.098

gMVP

0.11

Mutation Taster

=93/7

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