14-55428858-C-G

Position:

• chr14-55428858-C-G

Variant summary

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

The NM_199047.3(TBPL2):​c.809G>C​(p.Arg270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBPL2 NM_199047.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

Genes affected

TBPL2 (HGNC:19841): (TATA-box binding protein like 2) Predicted to enable RNA polymerase II general transcription initiation factor activity. Predicted to be involved in DNA-templated transcription, initiation. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FBXO34 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBPL2	NM_199047.3	c.809G>C	p.Arg270Thr	missense_variant	5/7	ENST00000247219.6	NP_950248.2
FBXO34	XR_007064022.1	n.2982+4774C>G		intron_variant
FBXO34	XR_007064023.1	n.2941-13969C>G		intron_variant
FBXO34	XR_007064024.1	n.2982+4774C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBPL2	ENST00000247219.6	c.809G>C	p.Arg270Thr	missense_variant	5/7	1	NM_199047.3	ENSP00000247219.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Oct 10, 2023

The c.905G>C (p.R302T) alteration is located in exon 5 (coding exon 5) of the TBPL2 gene. This alteration results from a G to C substitution at nucleotide position 905, causing the arginine (R) at amino acid position 302 to be replaced by a threonine (T). 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	0.30
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.48	P
Vest4		0.58
MutPred		0.46		Gain of catalytic residue at D300 (P = 0);
MVP		0.44
MPC		0.48
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.55
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1885875254; hg19: chr14-55895576;