rs144634857

Variant names:

• chr22-37713346-G-A
• rs144634857
• NM_001039141.3:c.391G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):​c.391G>A​(p.Gly131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,613,934 control chromosomes in the GnomAD database, including 43 homozygotes. 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: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (38 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.333
• Publications: 12 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

ENSG00000100101 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030972362).
• BP6: Variant 22-37713346-G-A is Benign according to our data. Variant chr22-37713346-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00456 (694/152242) while in subpopulation AMR AF = 0.00707 (108/15270). AF 95% confidence interval is 0.00599. There are 5 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	NM_001039141.3	MANE Select	c.391G>A	p.Gly131Ser	missense	Exon 5 of 24	NP_001034230.1	Q9H2D6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.391G>A	p.Gly131Ser	missense	Exon 5 of 24	ENSP00000496394.1	Q9H2D6-1
	ENSG00000100101	ENST00000455236.4	TSL:5	n.*727G>A		non_coding_transcript_exon	Exon 11 of 13	ENSP00000477208.1	V9GYY5
	ENSG00000100101	ENST00000455236.4	TSL:5	n.*727G>A		3_prime_UTR	Exon 11 of 13	ENSP00000477208.1	V9GYY5

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 693 AN: 152124 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00502 AC: 1252 AN: 249182 AF XY: 0.00517

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.00632

Gnomad OTH exome AF: 0.00677

GnomAD4 exome AF: 0.00516 AC: 7543 AN: 1461692 Hom.: 38 Cov.: 32 AF XY: 0.00525 AC XY: 3821 AN XY: 727148

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00344 AC: 154 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 723 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00245 AC: 211 AN: 86258

European-Finnish (FIN) AF: 0.000338 AC: 18 AN: 53296

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5768

European-Non Finnish (NFE) AF: 0.00526 AC: 5847 AN: 1111948

Other (OTH) AF: 0.00614 AC: 371 AN: 60382

GnomAD4 genome AF: 0.00456 AC: 694 AN: 152242 Hom.: 5 Cov.: 32 AF XY: 0.00453 AC XY: 337 AN XY: 74436

African (AFR) AF: 0.000914 AC: 38 AN: 41572

American (AMR) AF: 0.00707 AC: 108 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00553 AC: 376 AN: 68014

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00636 Hom.: 11

Bravo AF: 0.00499

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000939 AC: 4

ESP6500EA AF: 0.00693 AC: 59

ExAC AF: 0.00465 AC: 563

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00692

EpiControl AF: 0.00800

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.3
DANN	Benign	0.88
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.33
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.052
Sift	Benign	0.42	T
Sift4G	Benign	0.74	T
Polyphen		0.066	B
Vest4		0.14
MVP		0.14
MPC		0.12
ClinPred		0.00037	T
GERP RS		-4.6
Varity_R		0.014
gMVP		0.064
Mutation Taster		=100/0	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: rs144634857; hg19: chr22-38109353;