ENST00000407319.7:c.1259A>G

Variant names:

• chr22-37759490-A-G
• rs57799594
• ENST00000407319.7:c.1259A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000407319.7(TRIOBP):​c.1259A>G​(p.Lys420Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,603,498 control chromosomes in the GnomAD database, including 4,560 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (2412 hom., cov: 33)
  • Exomes 𝑓: 0.011 (2148 hom.)
• Consequence: TRIOBP ENST00000407319.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.39
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043314397).
• BP6: Variant 22-37759490-A-G is Benign according to our data. Variant chr22-37759490-A-G is described in ClinVar as Benign. ClinVar VariationId is 47853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000407319.7. 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.6324+226A>G		intron	N/A	NP_001034230.1
	TRIOBP	NM_138632.2		c.1259A>G	p.Lys420Arg	missense	Exon 8 of 8	NP_619538.2
	TRIOBP	NM_007032.5		c.1185+226A>G		intron	N/A	NP_008963.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000407319.7	TSL:1	c.1259A>G	p.Lys420Arg	missense	Exon 8 of 8	ENSP00000383913.2
	TRIOBP	ENST00000644935.1	MANE Select	c.6324+226A>G		intron	N/A	ENSP00000496394.1
	TRIOBP	ENST00000403663.6	TSL:1	c.1185+226A>G		intron	N/A	ENSP00000386026.2

Frequencies

GnomAD3 genomes AF: 0.0960 AC: 14599 AN: 152054 Hom.: 2405 Cov.: 33

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0357

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.0737

GnomAD2 exomes AF: 0.0274 AC: 6756 AN: 246744 AF XY: 0.0206

Gnomad AFR exome AF: 0.344

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000507

Gnomad NFE exome AF: 0.00309

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0113 AC: 16355 AN: 1451326 Hom.: 2148 Cov.: 29 AF XY: 0.00991 AC XY: 7160 AN XY: 722652

African (AFR) AF: 0.344 AC: 11460 AN: 33308

American (AMR) AF: 0.0204 AC: 913 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00859 AC: 224 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000860 AC: 74 AN: 86078

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51174

Middle Eastern (MID) AF: 0.0234 AC: 134 AN: 5732

European-Non Finnish (NFE) AF: 0.00196 AC: 2161 AN: 1104482

Other (OTH) AF: 0.0231 AC: 1388 AN: 60112

GnomAD4 genome AF: 0.0962 AC: 14636 AN: 152172 Hom.: 2412 Cov.: 33 AF XY: 0.0932 AC XY: 6936 AN XY: 74416

African (AFR) AF: 0.331 AC: 13710 AN: 41474

American (AMR) AF: 0.0356 AC: 544 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00278 AC: 189 AN: 67994

Other (OTH) AF: 0.0729 AC: 154 AN: 2112

Alfa AF: 0.0790 Hom.: 1146

Bravo AF: 0.109

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.324 AC: 1426

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.0327 AC: 3968

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00516

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lys420Arg in Exon 17A of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 32.4% (1210/3738) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs57799594).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.64
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.4
PROVEAN	Benign	0.99	N
REVEL	Benign	0.051
Sift	Uncertain	0.017	D
Sift4G	Benign	0.31	T
Vest4		0.11
ClinPred		0.013	T
GERP RS		2.9
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs57799594; hg19: chr22-38155497;