rs547759535

Positions:

• chr22-37734665-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001039141.3(TRIOBP):​c.4329A>G​(p.Leu1443Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,600,124 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.495

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 22-37734665-A-G is Benign according to our data. Variant chr22-37734665-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 165593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37734665-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.495 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.4329A>G	p.Leu1443Leu	synonymous_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.4329A>G	p.Leu1443Leu	synonymous_variant	9/24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000344404.10	n.*3812A>G		non_coding_transcript_exon_variant	7/22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*3812A>G		3_prime_UTR_variant	7/22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000544 AC: 118 AN: 216758 Hom.: 2 AF XY: 0.000544 AC XY: 65 AN XY: 119426

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.00884

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000701

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000189

Gnomad OTH exome AF: 0.000918

GnomAD4 exome AF: 0.000256 AC: 371 AN: 1447920 Hom.: 3 Cov.: 36 AF XY: 0.000268 AC XY: 193 AN XY: 719194

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000332

Gnomad4 ASJ exome AF: 0.00840

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000945

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000633

Gnomad4 OTH exome AF: 0.000969

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74416

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000932 Hom.: 0

Bravo AF: 0.000468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 31, 2013

Leu1443Leu in exon 9 of TRIOBP: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs547759535; hg19: chr22-38130672;