1-246565949-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_022366.3(TFB2M):c.190G>A(p.Ala64Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.006 in 1,614,216 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (43 hom.)
• Consequence: TFB2M NM_022366.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.43

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036287904).
• BP6: Variant 1-246565949-C-T is Benign according to our data. Variant chr1-246565949-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2640235.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFB2M	NM_022366.3	c.190G>A	p.Ala64Thr	missense_variant	1/8	ENST00000366514.5
TFB2M	XM_011544248.2	c.190G>A	p.Ala64Thr	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFB2M	ENST00000366514.5	c.190G>A	p.Ala64Thr	missense_variant	1/8	1	NM_022366.3	P1

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152206 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00803

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00528 AC: 1327 AN: 251490 Hom.: 9 AF XY: 0.00556 AC XY: 756 AN XY: 135920

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00494

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00768

Gnomad OTH exome AF: 0.00765

GnomAD4 exome AF: 0.00608 AC: 8894 AN: 1461892 Hom.: 43 Cov.: 31 AF XY: 0.00609 AC XY: 4432 AN XY: 727248

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00517

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00676

Gnomad4 OTH exome AF: 0.00679

GnomAD4 genome AF: 0.00515 AC: 785 AN: 152324 Hom.: 2 Cov.: 33 AF XY: 0.00467 AC XY: 348 AN XY: 74486

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00803

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00779 Hom.: 5

Bravo AF: 0.00558

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00492 AC: 597

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0101

EpiControl AF: 0.0111

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

TFB2M: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.14
Dann	Benign	0.76
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.0080
Sift	Benign	0.73	T
Sift4G	Benign	0.64	T
Polyphen		0.012	B
Vest4		0.091
MVP		0.22
MPC		0.15
ClinPred		0.0048	T
GERP RS		-7.9
Varity_R		0.038
gMVP		0.15

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: rs143880306; hg19: chr1-246729251; COSMIC: COSV63620412; COSMIC: COSV63620412;