rs1726790

Variant names:

• chr19-50408869-G-A
• rs1726790
• NM_002691.4:c.1860G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50408869-G-A
• chr19-50408869-G-T
• chr19-50408869-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.1860G>A​(p.Thr620Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,613,480 control chromosomes in the GnomAD database, including 524 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. T620T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.033 (277 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (247 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.17
• Publications: 7 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=-0.74).
• BP6: Variant 19-50408869-G-A is Benign according to our data. Variant chr19-50408869-G-A is described in ClinVar as Benign. ClinVar VariationId is 380638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 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.1860G>A	p.Thr620Thr	synonymous	Exon 15 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.1938G>A	p.Thr646Thr	synonymous	Exon 14 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.1860G>A	p.Thr620Thr	synonymous	Exon 15 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.1860G>A	p.Thr620Thr	synonymous	Exon 15 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.1938G>A	p.Thr646Thr	synonymous	Exon 15 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.1860G>A	p.Thr620Thr	synonymous	Exon 15 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5010 AN: 152136 Hom.: 275 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

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: 0.000323

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.00878 AC: 2198 AN: 250274 AF XY: 0.00617

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00718

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00327 AC: 4777 AN: 1461226 Hom.: 247 Cov.: 34 AF XY: 0.00277 AC XY: 2015 AN XY: 726944

African (AFR) AF: 0.114 AC: 3814 AN: 33444

American (AMR) AF: 0.00800 AC: 357 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26096

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

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5766

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1111742

Other (OTH) AF: 0.00739 AC: 446 AN: 60356

GnomAD4 genome AF: 0.0330 AC: 5026 AN: 152254 Hom.: 277 Cov.: 32 AF XY: 0.0319 AC XY: 2373 AN XY: 74454

African (AFR) AF: 0.114 AC: 4732 AN: 41524

American (AMR) AF: 0.0143 AC: 218 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68030

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0156 Hom.: 171

Bravo AF: 0.0382

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.085
DANN	Benign	0.67
PhyloP100		-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: rs1726790; hg19: chr19-50912126;