NM_001039141.3:c.2149C>G

Variant names:

• chr22-37724705-C-G
• rs186620158
• NM_001039141.3:c.2149C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001039141.3(TRIOBP):​c.2149C>G​(p.Gln717Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,613,024 control chromosomes in the GnomAD database, including 13 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0036 (13 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: -3.66
• 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

ENSG00000100101 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028777122).
• BP6: Variant 22-37724705-C-G is Benign according to our data. Variant chr22-37724705-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286759.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00226 (342/151394) while in subpopulation NFE AF = 0.00374 (254/67892). AF 95% confidence interval is 0.00336. There are 0 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	NM_001039141.3	MANE Select	c.2149C>G	p.Gln717Glu	missense	Exon 7 of 24	NP_001034230.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.2149C>G	p.Gln717Glu	missense	Exon 7 of 24	ENSP00000496394.1
	ENSG00000100101	ENST00000455236.4	TSL:5	n.*2485C>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000477208.1
	TRIOBP	ENST00000492485.5	TSL:1	n.2083C>G		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 342 AN: 151268 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000708

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00374

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00219 AC: 547 AN: 249568 AF XY: 0.00213

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00343

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00358 AC: 5232 AN: 1461630 Hom.: 13 Cov.: 150 AF XY: 0.00339 AC XY: 2468 AN XY: 727128

African (AFR) AF: 0.000299 AC: 10 AN: 33468

American (AMR) AF: 0.000448 AC: 20 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 319 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86228

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00423 AC: 4702 AN: 1111906

Other (OTH) AF: 0.00255 AC: 154 AN: 60378

GnomAD4 genome AF: 0.00226 AC: 342 AN: 151394 Hom.: 0 Cov.: 29 AF XY: 0.00232 AC XY: 172 AN XY: 74012

African (AFR) AF: 0.000706 AC: 29 AN: 41096

American (AMR) AF: 0.00112 AC: 17 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.000285 AC: 3 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00374 AC: 254 AN: 67892

Other (OTH) AF: 0.00190 AC: 4 AN: 2102

Alfa AF: 0.00346 Hom.: 0

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00128 AC: 5

ESP6500EA AF: 0.00458 AC: 38

ExAC AF: 0.00200 AC: 242

EpiCase AF: 0.00273

EpiControl AF: 0.00290

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Autosomal recessive nonsyndromic hearing loss 28 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.64
DANN	Benign	0.36
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L
PhyloP100		-3.7
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.017
Sift	Benign	0.067	T
Sift4G	Benign	0.33	T
Polyphen		0.0030	B
Vest4		0.10
MVP		0.15
MPC		0.13
ClinPred		0.013	T
GERP RS		-9.1
Varity_R		0.065
gMVP		0.013
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: rs186620158; hg19: chr22-38120712;