NM_001141980.3:c.1249G>A

Variant names:

• chr15-43469998-C-T
• rs689647
• NM_001141980.3:c.1249G>A

Variant summary

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

The NM_001141980.3(TP53BP1):​c.1249G>A​(p.Gly417Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,390 control chromosomes in the GnomAD database, including 33,013 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 0.28 (10247 hom., cov: 32)
  • Exomes 𝑓: 0.14 (22766 hom.)
• Consequence: TP53BP1 NM_001141980.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 52 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=7.288852E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 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.1249G>A	p.Gly417Ser	missense	Exon 11 of 28	NP_001135452.1	Q12888-2
	TP53BP1	NM_001141979.3		c.1249G>A	p.Gly417Ser	missense	Exon 11 of 28	NP_001135451.1	Q12888-3
	TP53BP1	NM_005657.4		c.1234G>A	p.Gly412Ser	missense	Exon 11 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.1249G>A	p.Gly417Ser	missense	Exon 11 of 28	ENSP00000371475.5	Q12888-2
	TP53BP1	ENST00000450115.6	TSL:1	c.1249G>A	p.Gly417Ser	missense	Exon 11 of 28	ENSP00000393497.2	Q12888-3
	TP53BP1	ENST00000263801.7	TSL:1	c.1234G>A	p.Gly412Ser	missense	Exon 11 of 28	ENSP00000263801.3	Q12888-1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42769 AN: 151868 Hom.: 10211 Cov.: 32

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.0864

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.199 AC: 49938 AN: 251248 AF XY: 0.188

Gnomad AFR exome AF: 0.657

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.411

Gnomad FIN exome AF: 0.0817

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.143 AC: 209332 AN: 1461404 Hom.: 22766 Cov.: 32 AF XY: 0.144 AC XY: 104445 AN XY: 727016

African (AFR) AF: 0.670 AC: 22421 AN: 33464

American (AMR) AF: 0.212 AC: 9469 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5064 AN: 26132

East Asian (EAS) AF: 0.407 AC: 16170 AN: 39696

South Asian (SAS) AF: 0.218 AC: 18755 AN: 86226

European-Finnish (FIN) AF: 0.0822 AC: 4387 AN: 53388

Middle Eastern (MID) AF: 0.158 AC: 874 AN: 5526

European-Non Finnish (NFE) AF: 0.109 AC: 121570 AN: 1111882

Other (OTH) AF: 0.176 AC: 10622 AN: 60370

GnomAD4 genome AF: 0.282 AC: 42869 AN: 151986 Hom.: 10247 Cov.: 32 AF XY: 0.279 AC XY: 20700 AN XY: 74300

African (AFR) AF: 0.650 AC: 26928 AN: 41416

American (AMR) AF: 0.215 AC: 3277 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3464

East Asian (EAS) AF: 0.397 AC: 2049 AN: 5164

South Asian (SAS) AF: 0.236 AC: 1139 AN: 4820

European-Finnish (FIN) AF: 0.0864 AC: 913 AN: 10568

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.107 AC: 7254 AN: 67976

Other (OTH) AF: 0.240 AC: 506 AN: 2112

Alfa AF: 0.177 Hom.: 16450

Bravo AF: 0.311

TwinsUK AF: 0.103 AC: 383

ALSPAC AF: 0.119 AC: 459

ESP6500AA AF: 0.630 AC: 2774

ESP6500EA AF: 0.113 AC: 971

ExAC AF: 0.206 AC: 25011

Asia WGS AF: 0.342 AC: 1186 AN: 3478

EpiCase AF: 0.120

EpiControl AF: 0.121

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0000073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.074
Sift	Benign	0.049	D
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.066
ClinPred		0.019	T
GERP RS		5.3
Varity_R		0.070
gMVP		0.24
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: rs689647; hg19: chr15-43762196; COSMIC: COSV55496549;