chr7-45101995-G-A

Position:

• chr7-45101995-G-A

Variant summary

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

The ENST00000258770.8(TBRG4):​c.1397C>T​(p.Pro466Leu) variant causes a missense change. 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 ENST00000258770.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.54

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 (HGNC:):

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, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBRG4	NM_004749.4	c.1397C>T	p.Pro466Leu	missense_variant	8/11	ENST00000258770.8	NP_004740.2
TBRG4	NM_001261834.2	c.1430C>T	p.Pro477Leu	missense_variant	8/11		NP_001248763.1
TBRG4	NM_030900.4	c.1067C>T	p.Pro356Leu	missense_variant	6/9		NP_112162.1
TBRG4	NM_199122.3	c.1067C>T	p.Pro356Leu	missense_variant	6/9		NP_954573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBRG4	ENST00000258770.8	c.1397C>T	p.Pro466Leu	missense_variant	8/11	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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The c.1397C>T (p.P466L) alteration is located in exon 8 (coding exon 7) of the TBRG4 gene. This alteration results from a C to T substitution at nucleotide position 1397, causing the proline (P) at amino acid position 466 to be replaced by a leucine (L). 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	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;.;D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.9	D;D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.65
MutPred		0.77		Loss of glycosylation at P466 (P = 0.0268);.;.;Loss of glycosylation at P466 (P = 0.0268);
MVP		0.33
MPC		0.86
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.43
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr7-45141594;