rs689647

Positions:

• chr15-43469998-C-G
• chr15-43469998-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001141980.3(TP53BP1):​c.1249G>C​(p.Gly417Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: TP53BP1 NM_001141980.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06811476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53BP1	NM_001141980.3	c.1249G>C	p.Gly417Arg	missense_variant	11/28	ENST00000382044.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53BP1	ENST00000382044.9	c.1249G>C	p.Gly417Arg	missense_variant	11/28	1	NM_001141980.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.065	.;T;T;.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.068	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	.;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.10	N;N;N;N;N
REVEL	Benign	0.059
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;.
Polyphen		0.0080	B;B;.;.;.
Vest4		0.13
MutPred		0.26		.;Loss of glycosylation at S411 (P = 0.0641);.;.;.;
MVP		0.043
MPC		0.079
ClinPred		0.25	T
GERP RS		5.3
Varity_R		0.084
gMVP		0.25

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

Other links and lift over

dbSNP: rs689647; hg19: chr15-43762196; COSMIC: COSV55506613;