NM_001039141.3:c.6455C>T

Variant names:

• chr22-37765800-C-T
• rs534215753
• NM_001039141.3:c.6455C>T

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.6455C>T​(p.Thr2152Met) variant causes a missense change. The variant allele was found at a frequency of 0.00282 in 1,581,080 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2152T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (145 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.85
• 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)
• 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=0.0033282042).
• BP6: Variant 22-37765800-C-T is Benign according to our data. Variant chr22-37765800-C-T is described in ClinVar as Benign. ClinVar VariationId is 165610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00158 (225/142272) while in subpopulation SAS AF = 0.0485 (217/4474). AF 95% confidence interval is 0.0432. There are 7 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.6455C>T	p.Thr2152Met	missense	Exon 18 of 24	NP_001034230.1	Q9H2D6-1
	TRIOBP	NM_007032.5		c.1316C>T	p.Thr439Met	missense	Exon 8 of 14	NP_008963.3	Q9H2D6-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.6455C>T	p.Thr2152Met	missense	Exon 18 of 24	ENSP00000496394.1	Q9H2D6-1
	TRIOBP	ENST00000403663.6	TSL:1	c.1316C>T	p.Thr439Met	missense	Exon 8 of 14	ENSP00000386026.2	Q9H2D6-7
	TRIOBP	ENST00000344404.10	TSL:2	n.*5938C>T		non_coding_transcript_exon	Exon 16 of 22	ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 227 AN: 142154 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.000109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000626

Gnomad SAS AF: 0.0489

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00657 AC: 1317 AN: 200552 AF XY: 0.00881

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000968

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000226

Gnomad OTH exome AF: 0.00291

GnomAD4 exome AF: 0.00294 AC: 4232 AN: 1438808 Hom.: 145 Cov.: 31 AF XY: 0.00427 AC XY: 3054 AN XY: 714476

African (AFR) AF: 0.0000604 AC: 2 AN: 33140

American (AMR) AF: 0.0000946 AC: 4 AN: 42286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38766

South Asian (SAS) AF: 0.0479 AC: 3995 AN: 83472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46614

Middle Eastern (MID) AF: 0.00206 AC: 10 AN: 4860

European-Non Finnish (NFE) AF: 0.0000254 AC: 28 AN: 1104352

Other (OTH) AF: 0.00323 AC: 192 AN: 59498

GnomAD4 genome AF: 0.00158 AC: 225 AN: 142272 Hom.: 7 Cov.: 31 AF XY: 0.00223 AC XY: 154 AN XY: 69008

African (AFR) AF: 0.000109 AC: 4 AN: 36698

American (AMR) AF: 0.00 AC: 0 AN: 14052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.000628 AC: 3 AN: 4778

South Asian (SAS) AF: 0.0485 AC: 217 AN: 4474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9794

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

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65946

Other (OTH) AF: 0.00 AC: 0 AN: 1936

Alfa AF: 0.000383 Hom.: 1

Bravo AF: 0.000332

ExAC AF: 0.00625 AC: 738

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	TRIOBP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.61
MVP		0.44
MPC		0.54
ClinPred		0.073	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.27
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs534215753; hg19: chr22-38161807;