22-37765827-C-T

Position:

• chr22-37765827-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001039141.3(TRIOBP):​c.6472+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,509,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: TRIOBP NM_001039141.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.371

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 22-37765827-C-T is Benign according to our data. Variant chr22-37765827-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 165611.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 = 0.00527 (399/75780) while in subpopulation AFR AF= 0.0299 (377/12596). AF 95% confidence interval is 0.0274. There are 0 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.6472+10C>T		intron_variant		ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.1333+10C>T		intron_variant			NP_008963.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6472+10C>T		intron_variant			NM_001039141.3	ENSP00000496394	A2
TRIOBP	ENST00000403663.6	c.1333+10C>T		intron_variant		1		ENSP00000386026	P2
TRIOBP	ENST00000344404.10	c.*5955+10C>T		intron_variant, NMD_transcript_variant		2		ENSP00000340312

Frequencies

GnomAD3 genomes AF: 0.00526 AC: 398 AN: 75718 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0300

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00219

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000255

Gnomad OTH AF: 0.00273

GnomAD3 exomes AF: 0.00111 AC: 116 AN: 104946 Hom.: 1 AF XY: 0.000852 AC XY: 50 AN XY: 58706

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.000526

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000216

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000279 AC: 400 AN: 1433416 Hom.: 1 Cov.: 31 AF XY: 0.000232 AC XY: 165 AN XY: 711330

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.000355

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000726

Gnomad4 OTH exome AF: 0.000657

GnomAD4 genome AF: 0.00527 AC: 399 AN: 75780 Hom.: 0 Cov.: 27 AF XY: 0.00518 AC XY: 193 AN XY: 37230

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.00219

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000255

Gnomad4 OTH AF: 0.00270

Bravo AF: 0.00309

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 18, 2015	c.6472+10C>T in intron 18 of TRIOBP: This variant is not expected to have clinic al significance because it is not located within the conserved region of the spl ice consensus sequence and has been identified in 5.1% (40/774) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ). -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs369182277; hg19: chr22-38161834;