22-37723839-C-G

Position:

• chr22-37723839-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001039141.3(TRIOBP):​c.1283C>G​(p.Pro428Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,597,144 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00010 (6 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.0100

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]

ENSG00000100101 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008493006).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000239 (36/150396) while in subpopulation EAS AF= 0.00377 (19/5036). AF 95% confidence interval is 0.00247. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.1283C>G	p.Pro428Arg	missense_variant	7/24	ENST00000644935.1	NP_001034230.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.1283C>G	p.Pro428Arg	missense_variant	7/24		NM_001039141.3	ENSP00000496394.1
ENSG00000100101	ENST00000455236.4	n.*1619C>G		non_coding_transcript_exon_variant	13/13	5		ENSP00000477208.1
ENSG00000100101	ENST00000455236.4	n.*1619C>G		3_prime_UTR_variant	13/13	5		ENSP00000477208.1

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 36 AN: 150280 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00376

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00195

GnomAD3 exomes AF: 0.000136 AC: 34 AN: 249568 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135402

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00145

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000100 AC: 145 AN: 1446748 Hom.: 6 Cov.: 56 AF XY: 0.0000973 AC XY: 70 AN XY: 719756

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000732

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000545

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.000239 AC: 36 AN: 150396 Hom.: 0 Cov.: 27 AF XY: 0.000109 AC XY: 8 AN XY: 73440

Gnomad4 AFR AF: 0.000245

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00377

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00192

Alfa AF: 0.000432 Hom.: 0

Bravo AF: 0.000253

ExAC AF: 0.000174 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 09, 2022	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 428 of the TRIOBP protein (p.Pro428Arg). This variant is present in population databases (rs372134073, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with TRIOBP-related conditions. ClinVar contains an entry for this variant (Variation ID: 285798). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -

Autosomal recessive nonsyndromic hearing loss 28 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.40	.;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.94	N;.
REVEL	Benign	0.052
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0080	D;.
Polyphen		0.77	P;P
Vest4		0.26
MVP		0.34
MPC		0.45
ClinPred		0.042	T
GERP RS		1.5
Varity_R		0.056
gMVP		0.032

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: rs372134073; hg19: chr22-38119846;