rs878854541

chr19-50415737-G-A

Variant summary

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

The NM_002691.4(POLD1):c.2731G>A(p.Asp911Asn) variant causes a missense change. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D911D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93

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.2731G>A	p.Asp911Asn	missense_variant	22/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2731G>A	p.Asp911Asn	missense_variant	22/27	1	NM_002691.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405274 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 694766

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

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

Feb 27, 2022

This variant has not been reported in the literature in individuals affected with POLD1-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 239310). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 911 of the POLD1 protein (p.Asp911Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;.;.;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.4	M;.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.9	D;.;.;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.023	D;.;.;.
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		0.98	D;.;.;D
Vest4		0.49
MutPred		0.42		Gain of MoRF binding (P = 0.0363);.;.;Gain of MoRF binding (P = 0.0363);
MVP		0.71
MPC		1.6
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.84
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs878854541; hg19: chr19-50918994; COSMIC: COSV54529777; COSMIC: COSV54529777;