22-37759212-G-C

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.6272G>C(p.Ser2091Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,613,080 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (8 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.69

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=0.003343314).
• BP6: Variant 22-37759212-G-C is Benign according to our data. Variant chr22-37759212-G-C is described in ClinVar as [Benign]. Clinvar id is 43865.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 = 0.00397 (605/152220) while in subpopulation AFR AF= 0.0142 (588/41528). AF 95% confidence interval is 0.0132. There are 6 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.6272G>C	p.Ser2091Thr	missense_variant	17/24	ENST00000644935.1
TRIOBP	NM_007032.5	c.1133G>C	p.Ser378Thr	missense_variant	7/14
TRIOBP	NM_138632.2	c.1133G>C	p.Ser378Thr	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6272G>C	p.Ser2091Thr	missense_variant	17/24		NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1133G>C	p.Ser378Thr	missense_variant	7/14	1		P2
TRIOBP	ENST00000407319.7	c.1133G>C	p.Ser378Thr	missense_variant	7/8	1
TRIOBP	ENST00000344404.10	c.*5755G>C		3_prime_UTR_variant, NMD_transcript_variant	15/22	2

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 603 AN: 152100 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000884 AC: 220 AN: 248942 Hom.: 2 AF XY: 0.000658 AC XY: 89 AN XY: 135174

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.000492

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: 0.0000178

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000439 AC: 642 AN: 1460860 Hom.: 8 Cov.: 31 AF XY: 0.000383 AC XY: 278 AN XY: 726748

Gnomad4 AFR exome AF: 0.0159

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.00397 AC: 605 AN: 152220 Hom.: 6 Cov.: 31 AF XY: 0.00406 AC XY: 302 AN XY: 74444

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.0000858 Hom.: 0

Bravo AF: 0.00460

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00108 AC: 131

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: 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	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Ser2091Thr in Exon 17 of TRIOBP: This variant is not expected to have clinical s ignificance because it has been identified in 1.3% (50/3732) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs78758968). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.8
Dann	Benign	0.90
DEOGEN2	Benign	0.040	T;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.56	D
MetaRNN	Benign	0.0033	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.76	N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.67	N;.;N;N;.
REVEL	Benign	0.082
Sift	Benign	0.14	T;.;D;T;.
Sift4G	Benign	0.57	T;.;T;T;.
Polyphen		0.26	B;B;.;.;.
Vest4		0.22
MVP		0.23
MPC		0.14
ClinPred		0.0031	T
GERP RS		0.0092
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.091
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs78758968; hg19: chr22-38155219;