rs727504784

Variant names:

• chr22-37734957-G-A
• rs727504784
• NM_001039141.3:c.4621G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001039141.3(TRIOBP):​c.4621G>A​(p.Ala1541Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03263572).
• BP6: Variant 22-37734957-G-A is Benign according to our data. Variant chr22-37734957-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 179313.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.4621G>A	p.Ala1541Thr	missense_variant	Exon 9 of 24	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.4621G>A	p.Ala1541Thr	missense_variant	Exon 9 of 24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000344404.10	n.*4104G>A		non_coding_transcript_exon_variant	Exon 7 of 22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*4104G>A		3_prime_UTR_variant	Exon 7 of 22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala1541Thr in exon 9 of TRIOBP: This variant is not expected to have clinical si gnificance because the alanine (Ala) residue at position 1451 is not conserved a cross species with cow, microbat, and megabat having a threonine (Thr) at this p osition. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.2
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.47	.;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.60	N;N
PhyloP100		-1.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.47	N;.
REVEL	Benign	0.021
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.020	D;.
Polyphen		0.0050	B;B
Vest4		0.040
MutPred		0.095		Gain of glycosylation at A1541 (P = 0.036);Gain of glycosylation at A1541 (P = 0.036);
MVP		0.20
MPC		0.11
ClinPred		0.045	T
GERP RS		-3.7
Varity_R		0.084
gMVP		0.022
Mutation Taster		=97/3	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs727504784; hg19: chr22-38130964; COSMIC: COSV105234592;