chr12-102164565-A-C

Position:

• chr12-102164565-A-C

Variant summary

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

The NM_017915.5(PARPBP):​c.623A>C​(p.Asp208Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: PARPBP NM_017915.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

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=0.2560097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PARPBP	NM_017915.5	c.623A>C	p.Asp208Ala	missense_variant	5/11	ENST00000327680.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PARPBP	ENST00000327680.7	c.623A>C	p.Asp208Ala	missense_variant	5/11	2	NM_017915.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

The c.623A>C (p.D208A) alteration is located in exon 5 (coding exon 4) of the PARPBP gene. This alteration results from a A to C substitution at nucleotide position 623, causing the aspartic acid (D) at amino acid position 208 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T;T;T;.;T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;D;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N;D;.;D;D;D
REVEL	Benign	0.12
Sift	Benign	0.13	T;T;.;D;T;T
Sift4G	Uncertain	0.011	D;D;D;D;D;D
Polyphen		0.52	P;D;B;B;.;.
Vest4		0.30
MutPred		0.34		Gain of catalytic residue at F283 (P = 0.0228);.;.;.;.;.;
MVP		0.59
ClinPred		0.92	D
GERP RS		4.7
Varity_R		0.18
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1256956756; hg19: chr12-102558343;