15-43432448-T-G

Position:

• chr15-43432448-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.68

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]

ACMG classification

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/exons	MANE	Protein	UniProt
TP53BP1	NM_001141980.3	c.3421A>C	p.Lys1141Gln	missense_variant	17/28	ENST00000382044.9	NP_001135452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53BP1	ENST00000382044.9	c.3421A>C	p.Lys1141Gln	missense_variant	17/28	1	NM_001141980.3	ENSP00000371475	P4

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69842 AN: 151958 Hom.: 20795 Cov.: 32

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

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.: 39 AF XY: 0.330 AC XY: 239948 AN XY: 727194

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.: 32 AF XY: 0.453 AC XY: 33662 AN XY: 74358

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	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	18
DANN	Benign	0.31
DEOGEN2	Benign	0.063	.;T;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.41	T;T;T;T
MetaRNN	Benign	6.1e-7	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	.;N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.25	T
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	T
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

Other links and lift over

dbSNP: rs2602141; hg19: chr15-43724646; COSMIC: COSV55496532; COSMIC: COSV55496532;