rs1555793871

chr19-50417866-GCG-TGT

Variant summary

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

The NM_002691.4(POLD1):c.3243_3245delinsTGT(p.Met1081_Arg1082delinsIleVal) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.3243_3245delinsTGT	p.Met1081_Arg1082delinsIleVal	missense_variant	27/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.3243_3245delinsTGT	p.Met1081_Arg1082delinsIleVal	missense_variant	27/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

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

Invitae

Nov 04, 2017

In summary, this variant is a novel complex change with uncertain impact on protein function. 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. Experimental studies and prediction algorithms are not available for this complex variant, and the functional significance of replacing both amino acids is unknown. In addition, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of both missense changes (p.Met1081Ile: SIFT: "Deleterious", PolyPhen-2: "Benign", Align-GVGD: "Class C0"; and p.Arg1082Val: SIFT: "Deleterious", PolyPhen-2: "Probably Damaging", Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with POLD1-related disease. This variant is not present in population databases (ExAC no frequency). This complex sequence change replaces methionine with isoleucine at codon 1081 and arginine with valine at codon 1082 of the POLD1 protein (p.Met1081_Arg1082delinsIleVal). The methionine residue at codon 1081 is highly conserved and there is a small physicochemical difference between methionine and isoleucine. The arginine residue at codon 1082 is highly conserved and there is a moderate physicochemical difference between arginine and valine. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555793871; hg19: chr19-50921123;