rs28450766

Variant names:

• chr22-37734514-C-T
• rs28450766
• NM_001039141.3:c.4178C>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.4178C>T​(p.Pro1393Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,606,316 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (20 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.56
• 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), PanelApp Australia
• 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=0.0030569732).
• BP6: Variant 22-37734514-C-T is Benign according to our data. Variant chr22-37734514-C-T is described in ClinVar as Benign. ClinVar VariationId is 43856.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 = 0.00681 (1036/152228) while in subpopulation AFR AF = 0.0232 (964/41536). AF 95% confidence interval is 0.022. There are 13 homozygotes in GnomAd4. There are 506 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.4178C>T	p.Pro1393Leu	missense	Exon 9 of 24	NP_001034230.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.4178C>T	p.Pro1393Leu	missense	Exon 9 of 24	ENSP00000496394.1
	TRIOBP	ENST00000344404.10	TSL:2	n.*3661C>T		non_coding_transcript_exon	Exon 7 of 22	ENSP00000340312.6
	TRIOBP	ENST00000344404.10	TSL:2	n.*3661C>T		3_prime_UTR	Exon 7 of 22	ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00676 AC: 1029 AN: 152110 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00162 AC: 373 AN: 230630 AF XY: 0.00124

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000682

Gnomad OTH exome AF: 0.000710

GnomAD4 exome AF: 0.000754 AC: 1096 AN: 1454088 Hom.: 20 Cov.: 36 AF XY: 0.000627 AC XY: 453 AN XY: 722802

African (AFR) AF: 0.0244 AC: 815 AN: 33420

American (AMR) AF: 0.00158 AC: 69 AN: 43548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.000106 AC: 9 AN: 85160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51676

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.0000514 AC: 57 AN: 1109094

Other (OTH) AF: 0.00226 AC: 136 AN: 60068

GnomAD4 genome AF: 0.00681 AC: 1036 AN: 152228 Hom.: 13 Cov.: 32 AF XY: 0.00680 AC XY: 506 AN XY: 74418

African (AFR) AF: 0.0232 AC: 964 AN: 41536

American (AMR) AF: 0.00307 AC: 47 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67996

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00274 Hom.: 8

Bravo AF: 0.00761

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0195 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00179 AC: 216

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.094	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.12
Sift	Benign	0.059	T
Sift4G	Benign	0.064	T
Polyphen		0.0010	B
Vest4		0.054
MVP		0.26
MPC		0.12
ClinPred		0.0073	T
GERP RS		4.5
Varity_R		0.028
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs28450766; hg19: chr22-38130521;