15-43432448-T-G

Variant names:

• chr15-43432448-T-G
• rs2602141
• NM_001141980.3:c.3421A>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 79 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141980.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53BP1	NM_001141980.3	MANE Select	c.3421A>C	p.Lys1141Gln	missense	Exon 17 of 28	NP_001135452.1	Q12888-2
	TP53BP1	NM_001141979.3		c.3421A>C	p.Lys1141Gln	missense	Exon 17 of 28	NP_001135451.1	Q12888-3
	TP53BP1	NM_005657.4		c.3406A>C	p.Lys1136Gln	missense	Exon 17 of 28	NP_005648.1	Q12888-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53BP1	ENST00000382044.9	TSL:1 MANE Select	c.3421A>C	p.Lys1141Gln	missense	Exon 17 of 28	ENSP00000371475.5	Q12888-2
	TP53BP1	ENST00000450115.6	TSL:1	c.3421A>C	p.Lys1141Gln	missense	Exon 17 of 28	ENSP00000393497.2	Q12888-3
	TP53BP1	ENST00000263801.7	TSL:1	c.3406A>C	p.Lys1136Gln	missense	Exon 17 of 28	ENSP00000263801.3	Q12888-1

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

GnomAD2 exomes AF: 0.363 AC: 91322 AN: 251430 AF XY: 0.359

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 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

African (AFR) AF: 0.874 AC: 29263 AN: 33480

American (AMR) AF: 0.320 AC: 14303 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 10588 AN: 26134

East Asian (EAS) AF: 0.410 AC: 16259 AN: 39700

South Asian (SAS) AF: 0.449 AC: 38707 AN: 86248

European-Finnish (FIN) AF: 0.211 AC: 11250 AN: 53414

Middle Eastern (MID) AF: 0.420 AC: 2420 AN: 5768

European-Non Finnish (NFE) AF: 0.301 AC: 334543 AN: 1111916

Other (OTH) AF: 0.360 AC: 21736 AN: 60394

GnomAD4 genome AF: 0.460 AC: 69948 AN: 152076 Hom.: 20848 Cov.: 32 AF XY: 0.453 AC XY: 33662 AN XY: 74358

African (AFR) AF: 0.852 AC: 35353 AN: 41516

American (AMR) AF: 0.362 AC: 5520 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1388 AN: 3466

East Asian (EAS) AF: 0.399 AC: 2064 AN: 5176

South Asian (SAS) AF: 0.440 AC: 2127 AN: 4830

European-Finnish (FIN) AF: 0.208 AC: 2199 AN: 10570

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20045 AN: 67942

Other (OTH) AF: 0.429 AC: 906 AN: 2110

Alfa AF: 0.355 Hom.: 50953

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 v4.9

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
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	6.1e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	N
PhyloP100		3.7
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.083
Sift	Benign	1.0	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.070
ClinPred		0.0023	T
GERP RS		4.5
Varity_R		0.033
gMVP		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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