17-61404632-G-T

Variant names:

• chr17-61404632-G-T
• rs1555877071
• NM_005994.4:c.914G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005994.4(TBX2):​c.914G>T​(p.Arg305Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R305S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TBX2 NM_005994.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.42
• Publications: 0 publications found

Genes affected

TBX2 (HGNC:11597): (T-box transcription factor 2) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product is the human homolog of mouse Tbx2, and shares strong sequence similarity with Drosophila omb protein. Expression studies indicate that this gene may have a potential role in tumorigenesis as an immortalizing agent. Transcript heterogeneity due to alternative polyadenylation has been noted for this gene. [provided by RefSeq, Jul 2008]

TBX2-AS1 (HGNC:50355): (TBX2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005994.4. 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
	TBX2	NM_005994.4	MANE Select	c.914G>T	p.Arg305Leu	missense	Exon 5 of 7	NP_005985.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX2	ENST00000240328.4	TSL:1 MANE Select	c.914G>T	p.Arg305Leu	missense	Exon 5 of 7	ENSP00000240328.3	Q13207
	TBX2	ENST00000419047.5	TSL:1	n.*451G>T		non_coding_transcript_exon	Exon 5 of 7	ENSP00000404781.1	F8WCM9
	TBX2	ENST00000419047.5	TSL:1	n.*451G>T		3_prime_UTR	Exon 5 of 7	ENSP00000404781.1	F8WCM9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429056 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 707084

African (AFR) AF: 0.00 AC: 0 AN: 32470

American (AMR) AF: 0.00 AC: 0 AN: 41118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24324

East Asian (EAS) AF: 0.00 AC: 0 AN: 38994

South Asian (SAS) AF: 0.00 AC: 0 AN: 82134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094604

Other (OTH) AF: 0.00 AC: 0 AN: 58720

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.1	L
PhyloP100		7.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.066	T
Polyphen		0.98	D
Vest4		0.84
MutPred		0.34		Loss of MoRF binding (P = 0.0089)
MVP		0.64
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.71
gMVP		0.61
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs1555877071; hg19: chr17-59481993;