rs727505184

Positions:

• chr22-37734580-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001039141.3(TRIOBP):​c.4244G>A​(p.Ser1415Asn) 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. 14/20 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: 0.311

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044704437).
• BP6: Variant 22-37734580-G-A is Benign according to our data. Variant chr22-37734580-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 179872.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-37734580-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.4244G>A	p.Ser1415Asn	missense_variant	9/24	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.4244G>A	p.Ser1415Asn	missense_variant	9/24		NM_001039141.3	ENSP00000496394	A2
TRIOBP	ENST00000344404.10	c.*3727G>A		3_prime_UTR_variant, NMD_transcript_variant	7/22	2		ENSP00000340312

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 07, 2014

Ser1415Asn in exon 9 of TRIOBP: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, opossum, Tasmanian devil, and wallaby have an asparagine (Asn) at this pos ition. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.72
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.45	.;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.78	N;.
REVEL	Benign	0.092
Sift	Uncertain	0.0070	D;.
Sift4G	Benign	0.089	T;.
Polyphen		0.0	B;B
Vest4		0.021
MutPred		0.069		Loss of phosphorylation at S1415 (P = 0.0288);Loss of phosphorylation at S1415 (P = 0.0288);
MVP		0.28
MPC		0.20
ClinPred		0.063	T
GERP RS		1.6
Varity_R		0.14
gMVP		0.040

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727505184; hg19: chr22-38130587;