7-45102000-C-G

Variant names:

• chr7-45102000-C-G
• NM_004749.4:c.1392G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004749.4(TBRG4):​c.1392G>C​(p.Glu464Asp) 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 pathogenic 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: 0.858

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBRG4	NM_004749.4	c.1392G>C	p.Glu464Asp	missense_variant	Exon 8 of 11	ENST00000258770.8	NP_004740.2
TBRG4	NM_001261834.2	c.1425G>C	p.Glu475Asp	missense_variant	Exon 8 of 11		NP_001248763.1
TBRG4	NM_030900.4	c.1062G>C	p.Glu354Asp	missense_variant	Exon 6 of 9		NP_112162.1
TBRG4	NM_199122.3	c.1062G>C	p.Glu354Asp	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.1392G>C	p.Glu464Asp	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

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1392G>C (p.E464D) alteration is located in exon 8 (coding exon 7) of the TBRG4 gene. This alteration results from a G to C substitution at nucleotide position 1392, causing the glutamic acid (E) at amino acid position 464 to be replaced by an aspartic acid (D). 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	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T;.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	.;.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.63	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N;D;D;N
REVEL	Uncertain	0.33
Sift	Benign	0.11	T;D;D;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.89
MutPred		0.82		Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);
MVP		0.29
MPC		0.81
ClinPred		0.87	D
GERP RS		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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.

Other links and lift over

hg19: chr7-45141599;