Genetic Variant TBRG4:p.Arg622Cys (chr7-45100357-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004749.4(TBRG4):c.1864C>T(p.Arg622Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TBRG4
NM_004749.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.45

Variant links:

Genes affected

TBRG4 (HGNC:17443): (transforming growth factor beta regulator 4) Enables RNA binding activity. Involved in mitochondrial mRNA processing and regulation of mitochondrial mRNA stability. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

TBRG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28301108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBRG4	NM_004749.4 link	c.1864C>T	p.Arg622Cys	missense_variant	Exon 11 of 11	ENST00000258770.8	NP_004740.2	Q969Z0-1
TBRG4	NM_001261834.2 link	c.1897C>T	p.Arg633Cys	missense_variant	Exon 11 of 11		NP_001248763.1	B3KRS4B4DU42
TBRG4	NM_030900.4 link	c.1534C>T	p.Arg512Cys	missense_variant	Exon 9 of 9		NP_112162.1	Q969Z0-2
TBRG4	NM_199122.3 link	c.1534C>T	p.Arg512Cys	missense_variant	Exon 9 of 9		NP_954573.1	Q969Z0-2B3KM73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBRG4	ENST00000258770.8 link	c.1864C>T	p.Arg622Cys	missense_variant	Exon 11 of 11	1	NM_004749.4	ENSP00000258770.3		Q969Z0-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251172

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1864C>T (p.R622C) alteration is located in exon 11 (coding exon 10) of the TBRG4 gene. This alteration results from a C to T substitution at nucleotide position 1864, causing the arginine (R) at amino acid position 622 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.036

T;.;.;T

Eigen

Benign

0.19

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

.;.;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.2

D;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Uncertain

0.047

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.32

MutPred

0.47

Loss of MoRF binding (P = 0.0018);.;.;Loss of MoRF binding (P = 0.0018);

MVP

0.12

MPC

0.91

ClinPred

0.84

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over