rs777449279

Variant names:

• chr22-37758130-G-A
• rs777449279
• NM_001039141.3:c.6205G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039141.3(TRIOBP):​c.6205G>A​(p.Glu2069Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,458,588 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21209756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.6205G>A	p.Glu2069Lys	missense_variant	Exon 16 of 24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.1066G>A	p.Glu356Lys	missense_variant	Exon 6 of 14		NP_008963.3
TRIOBP	NM_138632.2	c.1066G>A	p.Glu356Lys	missense_variant	Exon 6 of 8		NP_619538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6205G>A	p.Glu2069Lys	missense_variant	Exon 16 of 24		NM_001039141.3	ENSP00000496394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 243696 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1458588 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725578

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4172

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111922

Other (OTH) AF: 0.00 AC: 0 AN: 60176

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu2069Lys variant in TRIOBP has not been previously reported in individua ls with hearing loss or in large population studies. Computational prediction to ols and conservation analyses suggest that the variant may not impact the protei n, though this information is not predictive enough to rule out pathogenicity. I n summary, the clinical significance of the p.Glu2069Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T;T;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	.;D;.;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	M;M;.;.;.
PhyloP100		4.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N;.;N;N;.
REVEL	Benign	0.014
Sift	Benign	0.058	T;.;T;T;.
Sift4G	Benign	0.12	T;.;T;T;.
Polyphen		0.68	P;P;.;.;.
Vest4		0.66
MutPred		0.23		Gain of ubiquitination at E2069 (P = 0.0039);Gain of ubiquitination at E2069 (P = 0.0039);.;.;.;
MVP		0.37
MPC		0.58
ClinPred		0.66	D
GERP RS		4.6
Varity_R		0.28
gMVP		0.30
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs777449279; hg19: chr22-38154137;