rs200850285

Positions:

• chr22-37772674-G-A
• chr22-37772674-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001039141.3(TRIOBP):​c.7010G>A​(p.Arg2337Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 5.55

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02940765).
• BP6: Variant 22-37772674-G-A is Benign according to our data. Variant chr22-37772674-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505078.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.7010G>A	p.Arg2337Gln	missense_variant	23/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.1871G>A	p.Arg624Gln	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.7010G>A	p.Arg2337Gln	missense_variant	23/24		NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1871G>A	p.Arg624Gln	missense_variant	13/14	1		P2
TRIOBP	ENST00000344404.10	c.*6493G>A		3_prime_UTR_variant, NMD_transcript_variant	21/22	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 249472 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135354

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000495 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 18, 2022	ClinVar contains an entry for this variant (Variation ID: 505078). This variant has not been reported in the literature in individuals affected with TRIOBP-related conditions. This variant is present in population databases (rs200850285, gnomAD 0.2%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2337 of the TRIOBP protein (p.Arg2337Gln). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TRIOBP p.Arg624Gln variant was identified in dbSNP (ID: rs200850285), ClinVar (classified as likely benign by Laboratory for Molecular Medicine) and LOVD 3.0 (classified as a VUS) but was not identified in the literature. The variant was identified in control databases in 27 of 249472 chromosomes at a frequency of 0.000108 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 21 of 10070 chromosomes (freq: 0.002085), Other in 2 of 6066 chromosomes (freq: 0.00033), South Asian in 1 of 30600 chromosomes (freq: 0.000033), Latino in 1 of 34520 chromosomes (freq: 0.000029) and European (non-Finnish) in 2 of 113246 chromosomes (freq: 0.000018), but was not observed in the African, East Asian, or European (Finnish) populations. The p.Arg624 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 02, 2016

p.Arg2337Gln in exon 23 of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 6 mammals have a Glutamine (Gln) at this position despite high nearby am ino acid conservation. It has been identified in 6/66534 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs200850285). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.
Eigen	Benign	-0.050
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Benign	0.077
Sift	Benign	0.12	T;.;T
Sift4G	Benign	0.16	T;.;T
Polyphen		0.23	B;B;.
Vest4		0.29
MutPred		0.19		Loss of MoRF binding (P = 0.0306);Loss of MoRF binding (P = 0.0306);.;
MVP		0.41
MPC		0.22
ClinPred		0.084	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.20

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200850285; hg19: chr22-38168681; COSMIC: COSV60380172;