NM_001039141.3:c.6899T>C

Variant names:

• chr22-37771699-T-C
• rs61737841
• NM_001039141.3:c.6899T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):​c.6899T>C​(p.Val2300Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0013 in 1,613,994 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (20 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.75
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063397586).
• BP6: Variant 22-37771699-T-C is Benign according to our data. Variant chr22-37771699-T-C is described in ClinVar as Benign. ClinVar VariationId is 43867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00678 (1031/152144) while in subpopulation AFR AF = 0.0232 (963/41496). AF 95% confidence interval is 0.022. There are 12 homozygotes in GnomAd4. There are 509 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	NM_001039141.3	MANE Select	c.6899T>C	p.Val2300Ala	missense	Exon 22 of 24	NP_001034230.1
	TRIOBP	NM_007032.5		c.1760T>C	p.Val587Ala	missense	Exon 12 of 14	NP_008963.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.6899T>C	p.Val2300Ala	missense	Exon 22 of 24	ENSP00000496394.1
	TRIOBP	ENST00000403663.6	TSL:1	c.1760T>C	p.Val587Ala	missense	Exon 12 of 14	ENSP00000386026.2
	TRIOBP	ENST00000344404.10	TSL:2	n.*6382T>C		non_coding_transcript_exon	Exon 20 of 22	ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1024 AN: 152028 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00159 AC: 398 AN: 249572 AF XY: 0.00117

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000729 AC: 1065 AN: 1461850 Hom.: 20 Cov.: 31 AF XY: 0.000604 AC XY: 439 AN XY: 727232

African (AFR) AF: 0.0243 AC: 815 AN: 33478

American (AMR) AF: 0.00154 AC: 69 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111984

Other (OTH) AF: 0.00219 AC: 132 AN: 60392

GnomAD4 genome AF: 0.00678 AC: 1031 AN: 152144 Hom.: 12 Cov.: 32 AF XY: 0.00684 AC XY: 509 AN XY: 74382

African (AFR) AF: 0.0232 AC: 963 AN: 41496

American (AMR) AF: 0.00308 AC: 47 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00243 Hom.: 16

Bravo AF: 0.00762

ESP6500AA AF: 0.0204 AC: 81

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00184 AC: 223

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 16, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Val2300Ala in Exon 22 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 1.8% (60/3292) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61737841).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.099
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.43
MPC		0.16
ClinPred		0.025	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.37
Mutation Taster		=76/24	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61737841; hg19: chr22-38167706;