7-45101926-A-T

Variant names:

• chr7-45101926-A-T
• rs1143462
• NM_004749.4:c.1466T>A

Variant summary

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

The NM_004749.4(TBRG4):​c.1466T>A​(p.Val489Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBRG4 NM_004749.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.286

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057390243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBRG4	NM_004749.4	c.1466T>A	p.Val489Glu	missense_variant	Exon 8 of 11	ENST00000258770.8	NP_004740.2
TBRG4	NM_001261834.2	c.1499T>A	p.Val500Glu	missense_variant	Exon 8 of 11		NP_001248763.1
TBRG4	NM_030900.4	c.1136T>A	p.Val379Glu	missense_variant	Exon 6 of 9		NP_112162.1
TBRG4	NM_199122.3	c.1136T>A	p.Val379Glu	missense_variant	Exon 6 of 9		NP_954573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBRG4	ENST00000258770.8	c.1466T>A	p.Val489Glu	missense_variant	Exon 8 of 11	1	NM_004749.4	ENSP00000258770.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1466T>A (p.V489E) alteration is located in exon 8 (coding exon 7) of the TBRG4 gene. This alteration results from a T to A substitution at nucleotide position 1466, causing the valine (V) at amino acid position 489 to be replaced by a glutamic acid (E). 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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0045	T;.;.;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.68	.;.;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.057	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.82	N;D;D;N
REVEL	Benign	0.065
Sift	Uncertain	0.010	D;T;T;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.34	B;D;D;B
Vest4		0.17
MutPred		0.45		Gain of solvent accessibility (P = 0.0078);.;.;Gain of solvent accessibility (P = 0.0078);
MVP		0.043
MPC		0.39
ClinPred		0.33	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.093
gMVP		0.36

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: rs1143462; hg19: chr7-45141525;