rs200990219

Positions:

• chr22-37733304-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_001039141.3(TRIOBP):​c.3954C>T​(p.Ser1318Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,550,562 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.83

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 22-37733304-C-T is Benign according to our data. Variant chr22-37733304-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00146 (223/152316) while in subpopulation AFR AF= 0.00498 (207/41564). AF 95% confidence interval is 0.00442. There are 1 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.3954C>T	p.Ser1318Ser	synonymous_variant	8/24	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.3954C>T	p.Ser1318Ser	synonymous_variant	8/24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000344404.10	n.*3437C>T		non_coding_transcript_exon_variant	6/22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*3437C>T		3_prime_UTR_variant	6/22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00497

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000390 AC: 60 AN: 153722 Hom.: 1 AF XY: 0.000281 AC XY: 23 AN XY: 81818

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.0000810

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: 0.0000337

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000180 AC: 251 AN: 1398246 Hom.: 1 Cov.: 30 AF XY: 0.000139 AC XY: 96 AN XY: 689678

Gnomad4 AFR exome AF: 0.00617

Gnomad4 AMR exome AF: 0.000252

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000207

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.00152 AC XY: 113 AN XY: 74476

Gnomad4 AFR AF: 0.00498

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000867 Hom.: 0

Bravo AF: 0.00180

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 08, 2016

p.Ser1318Ser in exon 8 of TRIOBP: This variant is not expected to have clinical significance because it does not alter an amino acid residue, it is not located within the splice consensus sequence, and it has been identified in 0.6% (10/160 8) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs200990219). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200990219; hg19: chr22-38129311;