Genetic Variant TP53BP1:p.Lys1141Gln (chr15-43432448-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001141980.3(TP53BP1):c.3421A>C(p.Lys1141Gln) variant causes a missense change. The variant allele was found at a frequency of 0.34 in 1,613,854 control chromosomes in the GnomAD database, including 107,004 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 20848 hom., cov: 32)

Exomes 𝑓: 0.33 ( 86156 hom. )

Consequence

TP53BP1
NM_001141980.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.68

Variant links:

Genes affected

TP53BP1 (HGNC:11999): (tumor protein p53 binding protein 1) This gene encodes a protein that functions in the DNA double-strand break repair pathway choice, promoting non-homologous end joining (NHEJ) pathways, and limiting homologous recombination. This protein plays multiple roles in the DNA damage response, including promoting checkpoint signaling following DNA damage, acting as a scaffold for recruitment of DNA damage response proteins to damaged chromatin, and promoting NHEJ pathways by limiting end resection following a double-strand break. These roles are also important during V(D)J recombination, class switch recombination and at unprotected telomeres. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

TP53BP1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.1173375E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53BP1	NM_001141980.3 link	c.3421A>C	p.Lys1141Gln	missense_variant	Exon 17 of 28	ENST00000382044.9	NP_001135452.1	Q12888-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53BP1	ENST00000382044.9 link	c.3421A>C	p.Lys1141Gln	missense_variant	Exon 17 of 28	1	NM_001141980.3	ENSP00000371475.5		Q12888-2

Frequencies

GnomAD3 genomes

AF:

0.460

AC:

69842

AN:

151958

Hom.:

20795

Cov.:

show subpopulations

Gnomad AFR

AF:

0.851

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.362

Gnomad ASJ

AF:

0.400

Gnomad EAS

AF:

0.399

Gnomad SAS

AF:

0.441

Gnomad FIN

AF:

0.208

Gnomad MID

AF:

0.468

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.428

GnomAD3 exomes

AF:

0.363

AC:

91322

AN:

251430

Hom.:

19467

AF XY:

0.359

AC XY:

48821

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.859

Gnomad AMR exome

AF:

0.318

Gnomad ASJ exome

AF:

0.405

Gnomad EAS exome

AF:

0.414

Gnomad SAS exome

AF:

0.450

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.335

GnomAD4 exome

AF:

0.328

AC:

479069

AN:

1461778

Hom.:

86156

Cov.:

AF XY:

0.330

AC XY:

239948

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.874

Gnomad4 AMR exome

AF:

0.320

Gnomad4 ASJ exome

AF:

0.405

Gnomad4 EAS exome

AF:

0.410

Gnomad4 SAS exome

AF:

0.449

Gnomad4 FIN exome

AF:

0.211

Gnomad4 NFE exome

AF:

0.301

Gnomad4 OTH exome

AF:

0.360

GnomAD4 genome

AF:

0.460

AC:

69948

AN:

152076

Hom.:

20848

Cov.:

AF XY:

0.453

AC XY:

33662

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.852

Gnomad4 AMR

AF:

0.362

Gnomad4 ASJ

AF:

0.400

Gnomad4 EAS

AF:

0.399

Gnomad4 SAS

AF:

0.440

Gnomad4 FIN

AF:

0.208

Gnomad4 NFE

AF:

0.295

Gnomad4 OTH

AF:

0.429

Alfa

AF:

0.341

Hom.:

25198

Bravo

AF:

0.489

TwinsUK

AF:

0.296

AC:

1098

ALSPAC

AF:

0.305

AC:

1175

ESP6500AA

AF:

0.835

AC:

3676

ESP6500EA

AF:

0.304

AC:

2610

ExAC

AF:

0.375

AC:

45525

Asia WGS

AF:

0.437

AC:

1523

AN:

3478

EpiCase

AF:

0.314

EpiControl

AF:

0.313

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.31

DEOGEN2

Benign

0.063

.;T;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.41

T;T;T;T

MetaRNN

Benign

6.1e-7

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.3

.;N;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

1.1

N;N;N;N

REVEL

Benign

0.083

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.89

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.045

MPC

0.070

ClinPred

0.0023

GERP RS

4.5

Varity_R

0.033

gMVP

0.30

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over