rs774610362

chr22-37740976-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001039141.3(TRIOBP):c.5266C>T(p.Arg1756Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,560,616 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.46

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]

LOC124905115 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045862228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.5266C>T	p.Arg1756Trp	missense_variant	11/24	ENST00000644935.1
LOC124905115	XM_047441691.1	c.19-217G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.5266C>T	p.Arg1756Trp	missense_variant	11/24		NM_001039141.3	A2
TRIOBP	ENST00000344404.10	c.*4749C>T		3_prime_UTR_variant, NMD_transcript_variant	9/22	2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000678 AC: 11 AN: 162328 Hom.: 0 AF XY: 0.0000925 AC XY: 8 AN XY: 86474

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000824

Gnomad SAS exome AF: 0.0000429

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000334 AC: 47 AN: 1408384 Hom.: 0 Cov.: 33 AF XY: 0.0000388 AC XY: 27 AN XY: 695350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000919

Gnomad4 SAS exome AF: 0.0000376

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000923

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74362

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000277 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.0000779 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 21, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Arg1756Trp va riant in TRIOBP has not been previously reported in individuals with hearing los s, but was identified in 0.3% (3/1166) of East Asian chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org). Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, while the clinical significance of the p.Arg1756Trp variant is uncertain, its frequency in the East Asian population su ggests that it is more likely to be benign. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.51	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.95	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;D
Vest4		0.55
MutPred		0.38		Loss of disorder (P = 0.0122);Loss of disorder (P = 0.0122);
MVP		0.56
MPC		0.49
ClinPred		0.32	T
GERP RS		3.0
Varity_R		0.21
gMVP		0.24

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs774610362; hg19: chr22-38136983;