rs772763056

Variant names:

• chr19-50415806-G-A
• rs772763056
• NM_002691.4:c.2800G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50415806-G-A
• chr19-50415806-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002691.4(POLD1):​c.2800G>A​(p.Ala934Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000503 in 1,392,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A934A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.63
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• POLD1-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 10

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 120

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• non-severe combined immunodeficiency due to polymerase delta deficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2800G>A	p.Ala934Thr	missense_variant	Exon 22 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2800G>A	p.Ala934Thr	missense_variant	Exon 22 of 27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 10	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000124 AC: 2 AN: 160798 AF XY: 0.0000116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000303

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000503 AC: 7 AN: 1392502 Hom.: 0 Cov.: 33 AF XY: 0.00000291 AC XY: 2 AN XY: 686888

African (AFR) AF: 0.00 AC: 0 AN: 31998

American (AMR) AF: 0.00 AC: 0 AN: 35318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23684

East Asian (EAS) AF: 0.00 AC: 0 AN: 37560

South Asian (SAS) AF: 0.00 AC: 0 AN: 77866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3960

European-Non Finnish (NFE) AF: 0.00000649 AC: 7 AN: 1078496

Other (OTH) AF: 0.00 AC: 0 AN: 57386

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000857 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Colorectal cancer, susceptibility to, 10 Uncertain:1

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 934 of the POLD1 protein (p.Ala934Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 579980). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLD1 protein function with a positive predictive value of 80%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A934T variant (also known as c.2800G>A), located in coding exon 21 of the POLD1 gene, results from a G to A substitution at nucleotide position 2800. The alanine at codon 934 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.;L
PhyloP100		5.6
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.4	N;.;.;.
REVEL	Benign	0.080
Sift	Benign	0.086	T;.;.;.
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.26	B;.;.;B
Vest4		0.61
MutPred		0.31		Loss of ubiquitination at K931 (P = 0.1083);.;.;Loss of ubiquitination at K931 (P = 0.1083);
MVP		0.50
MPC		1.5
ClinPred		0.79	D
GERP RS		3.3
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.51
gMVP		0.42
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs772763056; hg19: chr19-50919063;