rs878854533

Positions:

• chr19-50413519-A-G

Variant summary

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

The NM_002691.4(POLD1):​c.2248A>G​(p.Lys750Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLD1 NM_002691.4 missense, splice_region
• Scores: Splicing: ADA: 0.1132
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.11

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]

POLD1 (HGNC:):

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=0.38810727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2248A>G	p.Lys750Glu	missense_variant, splice_region_variant	18/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2248A>G	p.Lys750Glu	missense_variant, splice_region_variant	18/27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 750 of the POLD1 protein (p.Lys750Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 239276). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.043
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.45	N;.;.;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.6	N;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.74	T;.;.;.
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.022	B;.;.;B
Vest4		0.56
MutPred		0.65		Loss of methylation at K750 (P = 0.0164);.;.;Loss of methylation at K750 (P = 0.0164);
MVP		0.57
MPC		1.7
ClinPred		0.93	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 45

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854533; hg19: chr19-50916776;