rs577534147

Positions:

• chr22-37768190-G-A

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.6575+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,600,954 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (4 hom.)
• Consequence: TRIOBP NM_001039141.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.38

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 (BayesDel_noAF=-0.87).
• BP6: Variant 22-37768190-G-A is Benign according to our data. Variant chr22-37768190-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 228041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000171 (26/152268) while in subpopulation SAS AF= 0.00456 (22/4828). AF 95% confidence interval is 0.00308. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.6575+14G>A		intron_variant		ENST00000644935.1
TRIOBP	NM_007032.5	c.1436+14G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6575+14G>A		intron_variant			NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1436+14G>A		intron_variant		1		P2
TRIOBP	ENST00000344404.10	c.*6058+14G>A		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000582 AC: 134 AN: 230284 Hom.: 1 AF XY: 0.000769 AC XY: 96 AN XY: 124778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000593

Gnomad SAS exome AF: 0.00430

Gnomad FIN exome AF: 0.000300

Gnomad NFE exome AF: 0.0000291

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000276 AC: 400 AN: 1448686 Hom.: 4 Cov.: 31 AF XY: 0.000403 AC XY: 290 AN XY: 719952

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00429

Gnomad4 FIN exome AF: 0.000190

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000717 Hom.: 0

Bravo AF: 0.0000302

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

c.6575+14G>A in intron 19 of TRIOBP: This variant is not expected to have clinic al significance because it has been identified in 0.6% (69/11848) of South Asian chromosomes including 1 homozygote by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org) -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.085
DANN	Benign	0.72

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs577534147; hg19: chr22-38164197;