rs1555790579

Variant names:

• chr19-50403560-A-C
• rs1555790579
• NM_002691.4:c.1205A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-50403560-A-C
• chr19-50403560-A-G
• chr19-50403560-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_002691.4(POLD1):​c.1205A>C​(p.Asp402Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87

Genes affected

POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a mutagenesis_site Loss of exonuclease activity. No effect on DNA polymerase activity. (size 0) in uniprot entity DPOD1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1205A>C	p.Asp402Ala	missense_variant	Exon 10 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1205A>C	p.Asp402Ala	missense_variant	Exon 10 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D402A variant (also known as c.1205A>C), located in coding exon 9 of the POLD1 gene, results from an A to C substitution at nucleotide position 1205. The aspartic acid at codon 402 is replaced by alanine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.7	H;.;.;H
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.6	D;.;.;.
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.95
MutPred		0.94		Gain of catalytic residue at D402 (P = 0.0781);Gain of catalytic residue at D402 (P = 0.0781);Gain of catalytic residue at D402 (P = 0.0781);Gain of catalytic residue at D402 (P = 0.0781);
MVP		0.86
MPC		1.8
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.99
gMVP		0.98

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: rs1555790579; hg19: chr19-50906817;