rs4821708

Variant names:

• chr22-37768099-C-T
• rs4821708
• NM_001039141.3:c.6498C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001039141.3(TRIOBP):​c.6498C>T​(p.Tyr2166Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,611,854 control chromosomes in the GnomAD database, including 77,257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5711 hom., cov: 31)
  • Exomes 𝑓: 0.31 (71546 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.04
• Publications: 29 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 22-37768099-C-T is Benign according to our data. Variant chr22-37768099-C-T is described in ClinVar as Benign. ClinVar VariationId is 43866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

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.6498C>T	p.Tyr2166Tyr	synonymous	Exon 19 of 24	NP_001034230.1	Q9H2D6-1
	TRIOBP	NM_007032.5		c.1359C>T	p.Tyr453Tyr	synonymous	Exon 9 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.6498C>T	p.Tyr2166Tyr	synonymous	Exon 19 of 24	ENSP00000496394.1	Q9H2D6-1
	TRIOBP	ENST00000403663.6	TSL:1	c.1359C>T	p.Tyr453Tyr	synonymous	Exon 9 of 14	ENSP00000386026.2	Q9H2D6-7
	TRIOBP	ENST00000344404.10	TSL:2	n.*5981C>T		non_coding_transcript_exon	Exon 17 of 22	ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38122 AN: 151928 Hom.: 5718 Cov.: 31

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.274

GnomAD2 exomes AF: 0.315 AC: 77487 AN: 246366 AF XY: 0.323

Gnomad AFR exome AF: 0.0701

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.290

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.323

GnomAD4 exome AF: 0.308 AC: 449136 AN: 1459808 Hom.: 71546 Cov.: 39 AF XY: 0.312 AC XY: 226162 AN XY: 725986

African (AFR) AF: 0.0665 AC: 2224 AN: 33456

American (AMR) AF: 0.324 AC: 14402 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9591 AN: 26116

East Asian (EAS) AF: 0.361 AC: 14287 AN: 39620

South Asian (SAS) AF: 0.399 AC: 34255 AN: 85930

European-Finnish (FIN) AF: 0.345 AC: 18409 AN: 53304

Middle Eastern (MID) AF: 0.340 AC: 1960 AN: 5766

European-Non Finnish (NFE) AF: 0.302 AC: 335764 AN: 1110892

Other (OTH) AF: 0.302 AC: 18244 AN: 60312

GnomAD4 genome AF: 0.251 AC: 38123 AN: 152046 Hom.: 5711 Cov.: 31 AF XY: 0.257 AC XY: 19069 AN XY: 74334

African (AFR) AF: 0.0752 AC: 3122 AN: 41518

American (AMR) AF: 0.298 AC: 4559 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 1311 AN: 3470

East Asian (EAS) AF: 0.299 AC: 1544 AN: 5156

South Asian (SAS) AF: 0.408 AC: 1967 AN: 4822

European-Finnish (FIN) AF: 0.342 AC: 3613 AN: 10558

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 21009 AN: 67932

Other (OTH) AF: 0.273 AC: 577 AN: 2112

Alfa AF: 0.299 Hom.: 11388

Bravo AF: 0.238

Asia WGS AF: 0.354 AC: 1229 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.2
DANN	Benign	0.85
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4821708; hg19: chr22-38164106; COSMIC: COSV60377009;