Genetic Variant TBRG1:p.Ala210Ser (chr11-124626940-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_032811.3(TBRG1):c.628G>T(p.Ala210Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A210T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TBRG1
NM_032811.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87

Variant links:

Genes affected

TBRG1 (HGNC:29551): (transforming growth factor beta regulator 1) Involved in several processes, including DNA replication; protein localization to nucleoplasm; and protein stabilization. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TBRG1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-124626940-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 996584.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.30535644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBRG1	NM_032811.3 link	c.628G>T	p.Ala210Ser	missense_variant	Exon 5 of 9	ENST00000441174.8	NP_116200.2	Q3YBR2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBRG1	ENST00000441174.8 link	c.628G>T	p.Ala210Ser	missense_variant	Exon 5 of 9	1	NM_032811.3	ENSP00000409016.3		Q3YBR2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453674

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722028

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.628G>T (p.A210S) alteration is located in exon 5 (coding exon 5) of the TBRG1 gene. This alteration results from a G to T substitution at nucleotide position 628, causing the alanine (A) at amino acid position 210 to be replaced by a serine (S). 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

0.096

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.23

.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.046

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.7

.;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.20

Sift

Benign

0.40

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.14

.;B

Vest4

0.64

MutPred

0.68

.;Gain of disorder (P = 0.0214);

MVP

0.86

MPC

0.056

ClinPred

0.65

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.14

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over