rs368349780

chr19-50408801-A-Cchr19-50408801-A-Gchr19-50408801-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002691.4(POLD1):c.1792A>C(p.Ile598Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I598T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.32

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.1792A>C	p.Ile598Leu	missense_variant	15/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.1792A>C	p.Ile598Leu	missense_variant	15/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.1	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.0	N;.;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.95	P;.;.;P
Vest4		0.72
MutPred		0.81		Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);
MVP		0.57
MPC		1.4
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.82
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50912058;