chr7-45101537-T-C

Variant names:

• chr7-45101537-T-C
• NM_004749.4:c.1645A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004749.4(TBRG4):​c.1645A>G​(p.Thr549Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBRG4 NM_004749.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.192
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026144624).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004749.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBRG4	NM_004749.4	MANE Select	c.1645A>G	p.Thr549Ala	missense	Exon 9 of 11	NP_004740.2
	TBRG4	NM_001261834.2		c.1678A>G	p.Thr560Ala	missense	Exon 9 of 11	NP_001248763.1	B4DU42
	TBRG4	NM_030900.4		c.1315A>G	p.Thr439Ala	missense	Exon 7 of 9	NP_112162.1	Q969Z0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBRG4	ENST00000258770.8	TSL:1 MANE Select	c.1645A>G	p.Thr549Ala	missense	Exon 9 of 11	ENSP00000258770.3	Q969Z0-1
	TBRG4	ENST00000361278.7	TSL:1	c.1315A>G	p.Thr439Ala	missense	Exon 7 of 9	ENSP00000354992.3	Q969Z0-2
	TBRG4	ENST00000495973.5	TSL:1	n.2934A>G		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461508 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727056

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.5
DANN	Benign	0.61
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.19
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.017
Sift	Benign	0.71	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.20		Loss of glycosylation at T549 (P = 0.0121)
MVP		0.068
MPC		0.22
ClinPred		0.042	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.49
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

hg19: chr7-45141136;