chr22-37758109-A-G

Variant names:

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

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.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. 16/22 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
• 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=0.027162343).
• 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 VariationId is 165604.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039141.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	NM_001039141.3	MANE Select	c.6184A>G	p.Ser2062Gly	missense	Exon 16 of 24	NP_001034230.1
	TRIOBP	NM_007032.5		c.1045A>G	p.Ser349Gly	missense	Exon 6 of 14	NP_008963.3
	TRIOBP	NM_138632.2		c.1045A>G	p.Ser349Gly	missense	Exon 6 of 8	NP_619538.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.6184A>G	p.Ser2062Gly	missense	Exon 16 of 24	ENSP00000496394.1
	TRIOBP	ENST00000403663.6	TSL:1	c.1045A>G	p.Ser349Gly	missense	Exon 6 of 14	ENSP00000386026.2
	TRIOBP	ENST00000407319.7	TSL:1	c.1045A>G	p.Ser349Gly	missense	Exon 6 of 8	ENSP00000383913.2

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

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: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4238

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60192

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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 v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.29	N
PhyloP100		-0.14
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.021
Sift	Benign	0.41	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.097		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
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs727503525; hg19: chr22-38154116;