rs61729063

Variant names:

• chr22-37768172-C-T
• rs61729063
• NM_001039141.3:c.6571C>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.6571C>T​(p.His2191Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,352 control chromosomes in the GnomAD database, including 15 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. H2191H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (9 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.06
• Publications: 4 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=0.0068521798).
• BP6: Variant 22-37768172-C-T is Benign according to our data. Variant chr22-37768172-C-T is described in ClinVar as Benign. ClinVar VariationId is 227127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00574 (874/152274) while in subpopulation AFR AF = 0.0198 (821/41546). AF 95% confidence interval is 0.0186. There are 6 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.6571C>T	p.His2191Tyr	missense	Exon 19 of 24	NP_001034230.1	Q9H2D6-1
	TRIOBP	NM_007032.5		c.1432C>T	p.His478Tyr	missense	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.6571C>T	p.His2191Tyr	missense	Exon 19 of 24	ENSP00000496394.1	Q9H2D6-1
	TRIOBP	ENST00000403663.6	TSL:1	c.1432C>T	p.His478Tyr	missense	Exon 9 of 14	ENSP00000386026.2	Q9H2D6-7
	TRIOBP	ENST00000344404.10	TSL:2	n.*6054C>T		non_coding_transcript_exon	Exon 17 of 22	ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 152156 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00128 AC: 311 AN: 242866 AF XY: 0.000979

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000910

Gnomad OTH exome AF: 0.000677

GnomAD4 exome AF: 0.000597 AC: 871 AN: 1459078 Hom.: 9 Cov.: 33 AF XY: 0.000528 AC XY: 383 AN XY: 725580

African (AFR) AF: 0.0181 AC: 604 AN: 33430

American (AMR) AF: 0.00133 AC: 59 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000945 AC: 105 AN: 1110710

Other (OTH) AF: 0.00158 AC: 95 AN: 60310

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152274 Hom.: 6 Cov.: 32 AF XY: 0.00564 AC XY: 420 AN XY: 74454

African (AFR) AF: 0.0198 AC: 821 AN: 41546

American (AMR) AF: 0.00216 AC: 33 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68032

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00224 Hom.: 4

Bravo AF: 0.00639

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0165 AC: 66

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00158 AC: 191

Asia WGS AF: 0.00202 AC: 7 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	L
PhyloP100		1.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.13
Sift	Benign	0.070	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.61
MVP		0.34
MPC		0.59
ClinPred		0.015	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.45
Mutation Taster		=91/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61729063; hg19: chr22-38164179;