rs138139146

Variant names:

• chr22-37769262-G-A
• rs138139146
• NM_001039141.3:c.6736G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):​c.6736G>A​(p.Glu2246Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00695 in 1,609,952 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (47 hom.)
• Consequence: TRIOBP NM_001039141.3 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.65
• Publications: 14 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 22-37769262-G-A is Benign according to our data. Variant chr22-37769262-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00472 (719/152374) while in subpopulation NFE AF = 0.007 (476/68028). AF 95% confidence interval is 0.00648. There are 5 homozygotes in GnomAd4. There are 344 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.6736G>A	p.Glu2246Lys	missense splice_region	Exon 21 of 24	NP_001034230.1
	TRIOBP	NM_007032.5		c.1597G>A	p.Glu533Lys	missense splice_region	Exon 11 of 14	NP_008963.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.6736G>A	p.Glu2246Lys	missense splice_region	Exon 21 of 24	ENSP00000496394.1
	TRIOBP	ENST00000403663.6	TSL:1	c.1597G>A	p.Glu533Lys	missense splice_region	Exon 11 of 14	ENSP00000386026.2
	TRIOBP	ENST00000344404.10	TSL:2	n.*6219G>A		splice_region non_coding_transcript_exon	Exon 19 of 22	ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 719 AN: 152256 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00700

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00532 AC: 1273 AN: 239260 AF XY: 0.00526

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00214

Gnomad NFE exome AF: 0.00765

Gnomad OTH exome AF: 0.00770

GnomAD4 exome AF: 0.00719 AC: 10478 AN: 1457578 Hom.: 47 Cov.: 33 AF XY: 0.00699 AC XY: 5067 AN XY: 724886

African (AFR) AF: 0.00141 AC: 47 AN: 33330

American (AMR) AF: 0.00545 AC: 242 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 422 AN: 26056

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39440

South Asian (SAS) AF: 0.000981 AC: 84 AN: 85608

European-Finnish (FIN) AF: 0.00171 AC: 89 AN: 52172

Middle Eastern (MID) AF: 0.00749 AC: 43 AN: 5738

European-Non Finnish (NFE) AF: 0.00820 AC: 9109 AN: 1110620

Other (OTH) AF: 0.00733 AC: 441 AN: 60172

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152374 Hom.: 5 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74510

African (AFR) AF: 0.00161 AC: 67 AN: 41594

American (AMR) AF: 0.00529 AC: 81 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00700 AC: 476 AN: 68028

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00643 Hom.: 2

Bravo AF: 0.00524

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00173 AC: 7

ESP6500EA AF: 0.00564 AC: 47

ExAC AF: 0.00490 AC: 592

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.84
MVP		0.55
MPC		0.58
ClinPred		0.017	T
GERP RS		4.4
Varity_R		0.37
gMVP		0.20
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92

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

Other links and lift over

dbSNP: rs138139146; hg19: chr22-38165269; COSMIC: COSV60374094;