rs61729063

chr22-37768172-C-T

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.6571C>T(p.His2191Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,352 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (9 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.06

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=0.0068521798).
• BP6: Variant 22-37768172-C-T is Benign according to our data. Variant chr22-37768172-C-T is described in ClinVar as [Benign]. Clinvar id is 227127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37768172-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00574 (874/152274) while in subpopulation AFR AF= 0.0198 (821/41546). AF 95% confidence interval is 0.0186. There are 6 homozygotes in gnomad4. There are 420 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.6571C>T	p.His2191Tyr	missense_variant	19/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.1432C>T	p.His478Tyr	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6571C>T	p.His2191Tyr	missense_variant	19/24		NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1432C>T	p.His478Tyr	missense_variant	9/14	1		P2
TRIOBP	ENST00000344404.10	c.*6054C>T		3_prime_UTR_variant, NMD_transcript_variant	17/22	2

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 152156 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00128 AC: 311 AN: 242866 Hom.: 1 AF XY: 0.000979 AC XY: 129 AN XY: 131756

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000674

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000910

Gnomad OTH exome AF: 0.000677

GnomAD4 exome AF: 0.000597 AC: 871 AN: 1459078 Hom.: 9 Cov.: 33 AF XY: 0.000528 AC XY: 383 AN XY: 725580

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.00133

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000945

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152274 Hom.: 6 Cov.: 32 AF XY: 0.00564 AC XY: 420 AN XY: 74454

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000994 Hom.: 1

Bravo AF: 0.00639

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0165 AC: 66

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00158 AC: 191

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	His2191Tyr in Exon 19 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 1.7% (57/3300) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs61729063). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D;.;D
REVEL	Benign	0.13
Sift	Benign	0.070	T;.;T
Sift4G	Benign	0.33	T;.;T
Polyphen		1.0	D;D;.
Vest4		0.61
MVP		0.34
MPC		0.59
ClinPred		0.015	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.45

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs61729063; hg19: chr22-38164179;