rs2230244

Variant names:

• chr19-50403528-C-A
• NM_002691.4:c.1173C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50403528-C-A
• chr19-50403528-C-G
• chr19-50403528-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002691.4(POLD1):​c.1173C>A​(p.Asp391Glu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D391D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.23

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1173C>A	p.Asp391Glu	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.1173C>A	p.Asp391Glu	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

Mar 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D391E variant (also known as c.1173C>A), located in coding exon 9 of the POLD1 gene, results from a C to A substitution at nucleotide position 1173. The aspartic acid at codon 391 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	2.2
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;.;D
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.081	N
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.4	M;.;.;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D;.;.;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.79
MutPred		0.90		Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);
MVP		0.31
MPC		1.6
ClinPred		0.99	D
GERP RS		-6.3
Varity_R		0.96
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50906785;