rs727503525

Variant names:

• chr22-37758109-A-G
• rs727503525
• NM_001039141.3:c.6184A>G

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.6184A>G​(p.Ser2062Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,814 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.136

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=0.027162343).
• BP6: Variant 22-37758109-A-G is Benign according to our data. Variant chr22-37758109-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 165604.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-37758109-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.6184A>G	p.Ser2062Gly	missense_variant	Exon 16 of 24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.1045A>G	p.Ser349Gly	missense_variant	Exon 6 of 14		NP_008963.3
TRIOBP	NM_138632.2	c.1045A>G	p.Ser349Gly	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.6184A>G	p.Ser2062Gly	missense_variant	Exon 16 of 24		NM_001039141.3	ENSP00000496394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458814 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 21, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser2062Gly in exon 16 of TRIOBP: This variant is not expected to have clinical s ignificance because the serine (Ser) at position 2062 is not conserved in mammal s or evolutionarily distant species and 16 mammals have a glycine (Gly) at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.6
DANN	Benign	0.68
DEOGEN2	Benign	0.015	T;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.61	.;T;.;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.29	N;N;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.050	N;.;N;N;.
REVEL	Benign	0.021
Sift	Benign	0.41	T;.;T;T;.
Sift4G	Benign	0.71	T;.;T;T;.
Polyphen		0.0	B;B;.;.;.
Vest4		0.12
MutPred		0.097		Loss of phosphorylation at S2062 (P = 0.0105);Loss of phosphorylation at S2062 (P = 0.0105);.;.;.;
MVP		0.19
MPC		0.11
ClinPred		0.019	T
GERP RS		-2.2
Varity_R		0.058
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503525; hg19: chr22-38154116;