rs918661445

chr19-50416643-C-Achr19-50416643-C-Gchr19-50416643-C-T

Variant summary

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

The NM_002691.4(POLD1):c.2987C>A(p.Thr996Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 1,413,694 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T996M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2987C>A	p.Thr996Lys	missense_variant	24/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2987C>A	p.Thr996Lys	missense_variant	24/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1413694 Hom.: 0 Cov.: 34 AF XY: 0.00000143 AC XY: 1 AN XY: 699996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.80	D;.;.;D
Eigen	Benign	-0.0055
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.9	D;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.074	T;.;.;.
Sift4G	Benign	0.077	T;T;T;T
Polyphen		0.48	P;.;.;P
Vest4		0.63
MutPred		0.50		Gain of MoRF binding (P = 0.0199);.;.;Gain of MoRF binding (P = 0.0199);
MVP		0.63
MPC		0.98
ClinPred		0.99	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.51
gMVP		0.57

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: chr19-50919900;