14-55433691-C-T

Position:

• chr14-55433691-C-T

Variant summary

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

The ENST00000247219.6(TBPL2):​c.631G>A​(p.Glu211Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E211G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TBPL2 ENST00000247219.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05

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.631G>A	p.Glu211Lys	missense_variant	4/7	ENST00000247219.6	NP_950248.2
FBXO34	XR_007064022.1	n.2983-3225C>T		intron_variant, non_coding_transcript_variant
FBXO34	XR_007064023.1	n.2941-9136C>T		intron_variant, non_coding_transcript_variant
FBXO34	XR_007064024.1	n.2983-4251C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBPL2	ENST00000247219.6	c.631G>A	p.Glu211Lys	missense_variant	4/7	1	NM_199047.3	ENSP00000247219	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Jan 06, 2023

The c.727G>A (p.E243K) alteration is located in exon 4 (coding exon 4) of the TBPL2 gene. This alteration results from a G to A substitution at nucleotide position 727, causing the glutamic acid (E) at amino acid position 243 to be replaced by a lysine (K). 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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.85	P
Vest4		0.69
MutPred		0.53		Gain of catalytic residue at E243 (P = 2e-04);
MVP		0.65
MPC		0.39
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.76
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs200543944; hg19: chr14-55900409;