rs1726803

Variant names:

• chr19-50402053-G-A
• rs1726803
• NM_002691.4:c.518G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50402053-G-A
• chr19-50402053-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001308632.1(POLD1):​c.518G>A​(p.Ser173Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00539 in 1,614,076 control chromosomes in the GnomAD database, including 416 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S173R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (212 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (204 hom.)
• Consequence: POLD1 NM_001308632.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.63
• Publications: 14 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019380748).
• BP6: Variant 19-50402053-G-A is Benign according to our data. Variant chr19-50402053-G-A is described in ClinVar as Benign. ClinVar VariationId is 380634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308632.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.518G>A	p.Ser173Asn	missense	Exon 5 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.518G>A	p.Ser173Asn	missense	Exon 4 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.518G>A	p.Ser173Asn	missense	Exon 5 of 27	NP_001243778.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.518G>A	p.Ser173Asn	missense	Exon 5 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.518G>A	p.Ser173Asn	missense	Exon 5 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.518G>A	p.Ser173Asn	missense	Exon 5 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4435 AN: 152152 Hom.: 210 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00770 AC: 1934 AN: 251044 AF XY: 0.00540

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00291 AC: 4249 AN: 1461806 Hom.: 204 Cov.: 34 AF XY: 0.00245 AC XY: 1781 AN XY: 727224

African (AFR) AF: 0.101 AC: 3374 AN: 33476

American (AMR) AF: 0.00722 AC: 323 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.000103 AC: 114 AN: 1111972

Other (OTH) AF: 0.00659 AC: 398 AN: 60390

GnomAD4 genome AF: 0.0292 AC: 4452 AN: 152270 Hom.: 212 Cov.: 32 AF XY: 0.0281 AC XY: 2090 AN XY: 74464

African (AFR) AF: 0.101 AC: 4185 AN: 41534

American (AMR) AF: 0.0129 AC: 198 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68018

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0115 Hom.: 217

Bravo AF: 0.0340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0958 AC: 422

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00925 AC: 1123

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Colorectal cancer, susceptibility to, 10 (2)
-	-	2	not provided (2)
-	-	1	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	22
DANN	Benign	0.72
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.097
Sift	Benign	0.57	T
Sift4G	Benign	0.49	T
Polyphen		0.45	B
Vest4		0.20
MVP		0.54
MPC		0.29
ClinPred		0.033	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.58
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1726803; hg19: chr19-50905310; COSMIC: COSV70954823; COSMIC: COSV70954823;