19-50401785-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002691.4(POLD1):​c.324G>T​(p.Ala108Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,612,072 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A108A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0090 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• 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=-0.83).
• BP6: Variant 19-50401785-G-T is Benign according to our data. Variant chr19-50401785-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00896 (1363/152158) while in subpopulation AFR AF = 0.0302 (1252/41486). AF 95% confidence interval is 0.0288. There are 21 homozygotes in GnomAd4. There are 644 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AD,AR gene

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>T	p.Ala108Ala	synonymous	Exon 4 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.324G>T	p.Ala108Ala	synonymous	Exon 3 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.324G>T	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>T	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.324G>T	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.324G>T	p.Ala108Ala	synonymous	Exon 4 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1356 AN: 152040 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00248 AC: 608 AN: 245174 AF XY: 0.00220

Gnomad AFR exome AF: 0.0287

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00121 AC: 1769 AN: 1459914 Hom.: 28 Cov.: 34 AF XY: 0.00115 AC XY: 838 AN XY: 726412

African (AFR) AF: 0.0350 AC: 1171 AN: 33472

American (AMR) AF: 0.00237 AC: 106 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 79 AN: 26114

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

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51780

Middle Eastern (MID) AF: 0.00747 AC: 43 AN: 5758

European-Non Finnish (NFE) AF: 0.000160 AC: 178 AN: 1111794

Other (OTH) AF: 0.00293 AC: 177 AN: 60346

GnomAD4 genome AF: 0.00896 AC: 1363 AN: 152158 Hom.: 21 Cov.: 32 AF XY: 0.00865 AC XY: 644 AN XY: 74416

African (AFR) AF: 0.0302 AC: 1252 AN: 41486

American (AMR) AF: 0.00386 AC: 59 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67972

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.0000996 Hom.: 1571

EpiCase AF: 0.000382

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	2	Colorectal cancer, susceptibility to, 10 (2)
-	-	1	Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome (1)
-	-	1	Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.036
DANN	Benign	0.84
PhyloP100		-3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;