rs20582

Variant names:

• chr19-50401785-G-A
• rs20582
• NM_002691.4:c.324G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50401785-G-A
• chr19-50401785-G-T
• chr19-50401785-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002691.4(POLD1):​c.324G>A​(p.Ala108Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,611,890 control chromosomes in the GnomAD database, including 9,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A108A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2213 hom., cov: 32)
  • Exomes 𝑓: 0.087 (7425 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.89
• Publications: 20 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):

• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-50401785-G-A is Benign according to our data. Variant chr19-50401785-G-A is described in ClinVar as Benign. ClinVar VariationId is 380219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002691.4. 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.324G>A	p.Ala108Ala	synonymous	Exon 4 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.324G>A	p.Ala108Ala	synonymous	Exon 3 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.324G>A	p.Ala108Ala	synonymous	Exon 4 of 27	NP_001243778.1	P28340

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.324G>A	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.324G>A	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.324G>A	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21097 AN: 151992 Hom.: 2207 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0670

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.111 AC: 27177 AN: 245174 AF XY: 0.113

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.0404

Gnomad NFE exome AF: 0.0707

Gnomad OTH exome AF: 0.0999

GnomAD4 exome AF: 0.0869 AC: 126900 AN: 1459780 Hom.: 7425 Cov.: 34 AF XY: 0.0901 AC XY: 65460 AN XY: 726348

African (AFR) AF: 0.295 AC: 9884 AN: 33464

American (AMR) AF: 0.105 AC: 4702 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2761 AN: 26114

East Asian (EAS) AF: 0.167 AC: 6611 AN: 39696

South Asian (SAS) AF: 0.197 AC: 17018 AN: 86240

European-Finnish (FIN) AF: 0.0413 AC: 2138 AN: 51772

Middle Eastern (MID) AF: 0.146 AC: 839 AN: 5758

European-Non Finnish (NFE) AF: 0.0692 AC: 76948 AN: 1111686

Other (OTH) AF: 0.0994 AC: 5999 AN: 60340

GnomAD4 genome AF: 0.139 AC: 21131 AN: 152110 Hom.: 2213 Cov.: 32 AF XY: 0.138 AC XY: 10251 AN XY: 74382

African (AFR) AF: 0.291 AC: 12063 AN: 41462

American (AMR) AF: 0.103 AC: 1572 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3472

East Asian (EAS) AF: 0.153 AC: 789 AN: 5158

South Asian (SAS) AF: 0.200 AC: 966 AN: 4828

European-Finnish (FIN) AF: 0.0359 AC: 381 AN: 10620

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0671 AC: 4558 AN: 67962

Other (OTH) AF: 0.127 AC: 269 AN: 2114

Alfa AF: 0.0878 Hom.: 1571

Bravo AF: 0.153

EpiCase AF: 0.0748

EpiControl AF: 0.0763

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Colorectal cancer, susceptibility to, 10 (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Mandibular hypoplasia-deafness-progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.18
DANN	Benign	0.86
PhyloP100		-3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Mutation Taster		=100/0	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: rs20582; hg19: chr19-50905042; COSMIC: COSV70955193; COSMIC: COSV70955193;