Variant 6-133980193-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004865.4(TBPL1):c.68G>A(p.Arg23Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TBPL1
NM_004865.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.46

Variant links:

Genes affected

TBPL1 (HGNC:11589): (TATA-box binding protein like 1) This gene encodes a member of the TATA box-binding protein family. TATA box-binding proteins play a critical role in transcription by RNA polymerase II as components of the transcription factor IID (TFIID) complex. The encoded protein does not bind to the TATA box and initiates transcription from TATA-less promoters. This gene plays a critical role in spermatogenesis, and single nucleotide polymorphisms in this gene may be associated with male infertility. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 3. [provided by RefSeq, Nov 2011]

TBPL1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3618962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBPL1	NM_004865.4 linkuse as main transcript	c.68G>A	p.Arg23Lys	missense_variant	2/7	ENST00000237264.9	NP_004856.1	P62380
TBPL1	NM_001253676.2 linkuse as main transcript	c.68G>A	p.Arg23Lys	missense_variant	2/7		NP_001240605.1	P62380

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBPL1	ENST00000237264.9 linkuse as main transcript	c.68G>A	p.Arg23Lys	missense_variant	2/7	1	NM_004865.4	ENSP00000237264.3		P62380

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000808

AC:

AN:

247676

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133946

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000669

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457602

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724986

show subpopulations

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:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The c.68G>A (p.R23K) alteration is located in exon 2 (coding exon 1) of the TBPL1 gene. This alteration results from a G to A substitution at nucleotide position 68, causing the arginine (R) at amino acid position 23 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

Benign

0.18

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Benign

0.89

DEOGEN2

Benign

0.034

T;T;T;T;T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D;D;.;D

M_CAP

Benign

0.0031

MetaRNN

Benign

0.36

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.1

.;L;.;.;L;.

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-2.3

N;.;N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.98

T;.;T;T;T;T

Sift4G

Benign

0.74

T;T;D;T;T;T

Polyphen

0.20

.;B;.;.;B;.

Vest4

0.60, 0.59

MutPred

0.44

Gain of methylation at R23 (P = 0.0126);Gain of methylation at R23 (P = 0.0126);Gain of methylation at R23 (P = 0.0126);Gain of methylation at R23 (P = 0.0126);Gain of methylation at R23 (P = 0.0126);Gain of methylation at R23 (P = 0.0126);

MVP

0.59

MPC

1.3

ClinPred

0.38

GERP RS

5.9

Varity_R

0.31

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over