19-50398907-G-C

Position:

• chr19-50398907-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002691.4(POLD1):​c.56G>C​(p.Arg19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. R19H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.22

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2751521).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.56G>C	p.Arg19Pro	missense_variant	2/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.56G>C	p.Arg19Pro	missense_variant	2/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448142 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719014

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T;.;.;.;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	.;.;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N;.;.;.;N;.
MutationTaster	Benign	0.91	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N;.;.;.;.;.
REVEL	Benign	0.099
Sift	Benign	0.046	D;.;.;.;.;.
Sift4G	Benign	0.20	T;T;D;T;T;D
Polyphen		0.68	P;.;.;.;P;.
Vest4		0.45
MutPred		0.17		Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);Gain of relative solvent accessibility (P = 0.0275);
MVP		0.63
MPC		0.27
ClinPred		0.80	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.30
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs3218773; hg19: chr19-50902164;