1-246548579-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022366.3(TFB2M):c.824C>A(p.Thr275Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,170 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: 6.8e-7 (0 hom.)
• Consequence: TFB2M NM_022366.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.297

Genes affected

TFB2M (HGNC:18559): (transcription factor B2, mitochondrial) Enables mitochondrial transcription factor activity. Involved in transcription initiation from mitochondrial promoter. Located in mitochondrial nucleoid. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.074134946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFB2M	NM_022366.3	c.824C>A	p.Thr275Asn	missense_variant	6/8	ENST00000366514.5
TFB2M	XM_011544248.2	c.521C>A	p.Thr174Asn	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFB2M	ENST00000366514.5	c.824C>A	p.Thr275Asn	missense_variant	6/8	1	NM_022366.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250404 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135566

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461170 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Jun 28, 2023

The c.824C>A (p.T275N) alteration is located in exon 6 (coding exon 6) of the TFB2M gene. This alteration results from a C to A substitution at nucleotide position 824, causing the threonine (T) at amino acid position 275 to be replaced by an asparagine (N). 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	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.13
Dann	Benign	0.33
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.031
Sift	Benign	0.56	T
Sift4G	Benign	0.32	T
Polyphen		0.018	B
Vest4		0.17
MutPred		0.57		Gain of catalytic residue at T275 (P = 0.0097);
MVP		0.32
MPC		0.18
ClinPred		0.014	T
GERP RS		0.48
Varity_R		0.036
gMVP		0.29

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: rs767272722; hg19: chr1-246711881;