22-37734465-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001039141.3(TRIOBP):c.4129T>C(p.Trp1377Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.958 in 1,612,998 control chromosomes in the GnomAD database, including 741,157 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71501 hom., cov: 31)

Exomes 𝑓: 0.96 ( 669656 hom. )

Consequence

TRIOBP
NM_001039141.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.415

Publications

27 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)
hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

TRIOBP 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=7.24621E-7).

BP6

Variant 22-37734465-T-C is Benign according to our data. Variant chr22-37734465-T-C is described in ClinVar as Benign. ClinVar VariationId is 43855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.983 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039141.3. 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
	TRIOBP	NM_001039141.3	MANE Select	c.4129T>C	p.Trp1377Arg	missense	Exon 9 of 24	NP_001034230.1	Q9H2D6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRIOBP	ENST00000644935.1	MANE Select	c.4129T>C	p.Trp1377Arg	missense	Exon 9 of 24	ENSP00000496394.1	Q9H2D6-1
TRIOBP	ENST00000344404.10	TSL:2	n.*3612T>C		non_coding_transcript_exon	Exon 7 of 22	ENSP00000340312.6	H7BXW4
TRIOBP	ENST00000344404.10	TSL:2	n.*3612T>C		3_prime_UTR	Exon 7 of 22	ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes

AF:

0.969

AC:

147393

AN:

152124

Hom.:

71440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.991

Gnomad AMI

AF:

0.979

Gnomad AMR

AF:

0.968

Gnomad ASJ

AF:

0.910

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.997

Gnomad FIN

AF:

0.977

Gnomad MID

AF:

0.949

Gnomad NFE

AF:

0.953

Gnomad OTH

AF:

0.965

GnomAD2 exomes

AF:

0.966

AC:

238692

AN:

247150

AF XY:

0.966

show subpopulations

Gnomad AFR exome

AF:

0.991

Gnomad AMR exome

AF:

0.977

Gnomad ASJ exome

AF:

0.910

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.975

Gnomad NFE exome

AF:

0.949

Gnomad OTH exome

AF:

0.957

GnomAD4 exome

AF:

0.957

AC:

1398449

AN:

1460756

Hom.:

669656

Cov.:

AF XY:

0.958

AC XY:

696107

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.993

AC:

33248

AN:

33474

American (AMR)

AF:

0.976

AC:

43580

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.912

AC:

23817

AN:

26104

East Asian (EAS)

AF:

1.00

AC:

39695

AN:

39698

South Asian (SAS)

AF:

0.994

AC:

85643

AN:

86202

European-Finnish (FIN)

AF:

0.971

AC:

51139

AN:

52648

Middle Eastern (MID)

AF:

0.974

AC:

5618

AN:

5768

European-Non Finnish (NFE)

AF:

0.951

AC:

1057820

AN:

1111828

Other (OTH)

AF:

0.959

AC:

57889

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3735

7471

11206

14942

18677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21622

43244

64866

86488

108110

<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:

0.969

AC:

147513

AN:

152242

Hom.:

71501

Cov.:

AF XY:

0.970

AC XY:

72233

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.991

AC:

41181

AN:

41546

American (AMR)

AF:

0.968

AC:

14813

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.910

AC:

3159

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5158

AN:

5160

South Asian (SAS)

AF:

0.997

AC:

4806

AN:

4820

European-Finnish (FIN)

AF:

0.977

AC:

10372

AN:

10612

Middle Eastern (MID)

AF:

0.949

AC:

279

AN:

294

European-Non Finnish (NFE)

AF:

0.953

AC:

64814

AN:

68008

Other (OTH)

AF:

0.965

AC:

2040

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

244

488

733

977

1221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.956

Hom.:

159363

Bravo

AF:

0.969

TwinsUK

AF:

0.946

AC:

3506

ALSPAC

AF:

0.954

AC:

3676

ESP6500AA

AF:

0.989

AC:

3817

ESP6500EA

AF:

0.953

AC:

7866

ExAC

AF:

0.965

AC:

116460

Asia WGS

AF:

0.994

AC:

3458

AN:

3478

EpiCase

AF:

0.950

EpiControl

AF:

0.945

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Autosomal recessive nonsyndromic hearing loss 28 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.63

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.012

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.066

MetaRNN

Benign

7.2e-7

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

-0.41

PrimateAI

Benign

0.32

PROVEAN

Benign

3.0

REVEL

Benign

0.038

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.015

MutPred

0.10

Gain of methylation at W1377 (P = 0.0191)

MPC

0.21

ClinPred

0.0010

GERP RS

0.85

Varity_R

0.043

gMVP

0.042

Mutation Taster

=99/1

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over