rs61737841

Positions:

• chr22-37771699-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 43867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37771699-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.6899T>C	p.Val2300Ala	missense_variant	22/24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.1760T>C	p.Val587Ala	missense_variant	12/14		NP_008963.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6899T>C	p.Val2300Ala	missense_variant	22/24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000403663.6	c.1760T>C	p.Val587Ala	missense_variant	12/14	1		ENSP00000386026.2
TRIOBP	ENST00000344404.10	n.*6382T>C		non_coding_transcript_exon_variant	20/22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*6382T>C		3_prime_UTR_variant	20/22	2		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

GnomAD3 exomes AF: 0.00159 AC: 398 AN: 249572 Hom.: 3 AF XY: 0.00117 AC XY: 159 AN XY: 135408

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00219

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

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00136 Hom.: 4

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D;.;D
REVEL	Benign	0.099
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0030	D;.;T
Polyphen		1.0	D;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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61737841; hg19: chr22-38167706;