rs144175566

Positions:

• chr22-37734501-C-A
• chr22-37734501-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039141.3(TRIOBP):​c.4165C>A​(p.Leu1389Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,609,754 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (10 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.362

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003253758).
• BP6: Variant 22-37734501-C-A is Benign according to our data. Variant chr22-37734501-C-A is described in ClinVar as [Benign]. Clinvar id is 227125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37734501-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00581 (885/152272) while in subpopulation AFR AF= 0.02 (831/41556). AF 95% confidence interval is 0.0189. There are 6 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.4165C>A	p.Leu1389Ile	missense_variant	9/24	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.4165C>A	p.Leu1389Ile	missense_variant	9/24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000344404.10	n.*3648C>A		non_coding_transcript_exon_variant	7/22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*3648C>A		3_prime_UTR_variant	7/22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 881 AN: 152154 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0199

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: 0.000221

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00133 AC: 317 AN: 239056 Hom.: 1 AF XY: 0.00104 AC XY: 136 AN XY: 130824

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000673

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000931

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000606 AC: 883 AN: 1457482 Hom.: 10 Cov.: 36 AF XY: 0.000541 AC XY: 392 AN XY: 724754

Gnomad4 AFR exome AF: 0.0183

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000954

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00581 AC: 885 AN: 152272 Hom.: 6 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74446

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.00646

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0169 AC: 64

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00163 AC: 196

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Leu1389Ile in Exon 09 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 1.7% (53/3102) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs144175566). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.6
DANN	Benign	0.93
DEOGEN2	Benign	0.022	T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.42	.;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.70	N;.
REVEL	Benign	0.0080
Sift	Uncertain	0.010	D;.
Sift4G	Benign	0.28	T;.
Polyphen		0.34	B;B
Vest4		0.12
MVP		0.19
MPC		0.19
ClinPred		0.0028	T
GERP RS		-0.59
Varity_R		0.053
gMVP		0.032

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs144175566; hg19: chr22-38130508;