rs146823511

chr22-37759499-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The ENST00000407319.7(TRIOBP):c.1268C>T(p.Pro423Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,606,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P423P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: TRIOBP ENST00000407319.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.26

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013629794).
• BP6: Variant 22-37759499-C-T is Benign according to our data. Variant chr22-37759499-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504694.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.6324+235C>T		intron_variant		ENST00000644935.1
TRIOBP	NM_138632.2	c.1268C>T	p.Pro423Leu	missense_variant	8/8
TRIOBP	NM_007032.5	c.1185+235C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000407319.7	c.1268C>T	p.Pro423Leu	missense_variant	8/8	1
TRIOBP	ENST00000644935.1	c.6324+235C>T		intron_variant			NM_001039141.3	A2
TRIOBP	ENST00000403663.6	c.1185+235C>T		intron_variant		1		P2
TRIOBP	ENST00000344404.10	c.*5807+235C>T		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000150 AC: 37 AN: 246160 Hom.: 0 AF XY: 0.000172 AC XY: 23 AN XY: 133524

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000523

Gnomad NFE exome AF: 0.0000810

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 170 AN: 1454566 Hom.: 1 Cov.: 30 AF XY: 0.000112 AC XY: 81 AN XY: 724004

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000200

Gnomad4 NFE exome AF: 0.0000803

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74492

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000378

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 13, 2016

p.Pro423Leu in exon 17A of TRIOBP: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, >5 mammals have a leucine (Leu) at this position despite high nearby am ino acid conservation. In addition, computational prediction tools do not sugge st a high likelihood of impact to the protein. This variant has been identifie d in 0.1% (9/10336) of African chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs146823511). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.26
Dann	Benign	0.82
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.025	N
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	0.82	N;.
REVEL	Benign	0.026
Sift	Uncertain	0.017	D;.
Sift4G	Benign	0.50	T;.
Vest4		0.093
MVP		0.15
ClinPred		0.0048	T
GERP RS		-10

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: rs146823511; hg19: chr22-38155506;