15-43475576-G-C

Variant names:

• chr15-43475576-G-C
• rs560191
• NM_001141980.3:c.1074C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001141980.3(TP53BP1):​c.1074C>G​(p.Asp358Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,613,084 control chromosomes in the GnomAD database, including 107,421 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 (21371 hom., cov: 32)
  • Exomes 𝑓: 0.33 (86050 hom.)
• Consequence: TP53BP1 NM_001141980.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.167
• Publications: 73 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=5.580964E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53BP1	NM_001141980.3	c.1074C>G	p.Asp358Glu	missense_variant	Exon 9 of 28	ENST00000382044.9	NP_001135452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53BP1	ENST00000382044.9	c.1074C>G	p.Asp358Glu	missense_variant	Exon 9 of 28	1	NM_001141980.3	ENSP00000371475.5

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70394 AN: 152004 Hom.: 21315 Cov.: 32

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.362 AC: 90958 AN: 251344 AF XY: 0.357

Gnomad AFR exome AF: 0.873

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.414

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.333

GnomAD4 exome AF: 0.327 AC: 477809 AN: 1460960 Hom.: 86050 Cov.: 36 AF XY: 0.329 AC XY: 239030 AN XY: 726816

African (AFR) AF: 0.891 AC: 29821 AN: 33470

American (AMR) AF: 0.320 AC: 14287 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 10454 AN: 26124

East Asian (EAS) AF: 0.409 AC: 16250 AN: 39692

South Asian (SAS) AF: 0.435 AC: 37514 AN: 86220

European-Finnish (FIN) AF: 0.210 AC: 11240 AN: 53406

Middle Eastern (MID) AF: 0.419 AC: 2390 AN: 5706

European-Non Finnish (NFE) AF: 0.301 AC: 334157 AN: 1111260

Other (OTH) AF: 0.359 AC: 21696 AN: 60366

GnomAD4 genome AF: 0.463 AC: 70504 AN: 152124 Hom.: 21371 Cov.: 32 AF XY: 0.456 AC XY: 33915 AN XY: 74364

African (AFR) AF: 0.867 AC: 35984 AN: 41516

American (AMR) AF: 0.364 AC: 5557 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1373 AN: 3468

East Asian (EAS) AF: 0.398 AC: 2057 AN: 5168

South Asian (SAS) AF: 0.424 AC: 2045 AN: 4820

European-Finnish (FIN) AF: 0.208 AC: 2198 AN: 10586

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20037 AN: 67970

Other (OTH) AF: 0.430 AC: 908 AN: 2110

Alfa AF: 0.312 Hom.: 5838

Bravo AF: 0.494

TwinsUK AF: 0.297 AC: 1101

ALSPAC AF: 0.305 AC: 1177

ESP6500AA AF: 0.850 AC: 3740

ESP6500EA AF: 0.303 AC: 2604

ExAC AF: 0.374 AC: 45358

Asia WGS AF: 0.431 AC: 1501 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	0.069
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.53
DEOGEN2	Benign	0.0	.;T;T;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.13	T;T;T;T;T
MetaRNN	Benign	5.6e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.;.;.
PhyloP100		0.17
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.94	N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;.
Vest4		0.018
ClinPred		0.00061	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.021
gMVP		0.054
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs560191; hg19: chr15-43767774; COSMIC: COSV55496034;