12-102175665-G-A

Position:

• chr12-102175665-G-A

Variant summary

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

The NM_017915.5(PARPBP):​c.1004G>A​(p.Arg335Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 1,572,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: PARPBP NM_017915.5 missense, splice_region
• Scores: Splicing: ADA: 0.004646
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54

Genes affected

PARPBP (HGNC:26074): (PARP1 binding protein) Predicted to enable DNA binding activity. Involved in negative regulation of double-strand break repair via homologous recombination. Located in chromatin and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.098184705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PARPBP	NM_017915.5	c.1004G>A	p.Arg335Gln	missense_variant, splice_region_variant	7/11	ENST00000327680.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PARPBP	ENST00000327680.7	c.1004G>A	p.Arg335Gln	missense_variant, splice_region_variant	7/11	2	NM_017915.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000352 AC: 8 AN: 227016 Hom.: 0 AF XY: 0.0000487 AC XY: 6 AN XY: 123152

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000950

Gnomad NFE exome AF: 0.0000377

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000443 AC: 63 AN: 1420706 Hom.: 0 Cov.: 26 AF XY: 0.0000340 AC XY: 24 AN XY: 705656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.0000569

Gnomad4 NFE exome AF: 0.0000506

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74300

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000766 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.074	T;T;.
Eigen	Benign	-0.041
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.2	N;.;N
REVEL	Benign	0.10
Sift	Benign	0.17	T;.;T
Sift4G	Uncertain	0.026	D;D;D
Polyphen		0.21	B;P;.
Vest4		0.17
MVP		0.51
ClinPred		0.12	T
GERP RS		3.2
Varity_R		0.063
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0046
dbscSNV1_RF	Benign	0.27
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: rs373285188; hg19: chr12-102569443;