19-50403099-G-T

Variant names:

• chr19-50403099-G-T
• rs373404887
• NM_002691.4:c.1017G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_002691.4(POLD1):​c.1017G>T​(p.Ser339Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,564,842 control chromosomes in the GnomAD database, including 1 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. S339S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.78
• Publications: 1 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, Orphanet
• 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-50403099-G-T is Benign according to our data. Variant chr19-50403099-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.78 with no splicing effect.

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.1017G>T	p.Ser339Ser	synonymous	Exon 9 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.1017G>T	p.Ser339Ser	synonymous	Exon 8 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.1017G>T	p.Ser339Ser	synonymous	Exon 9 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.1017G>T	p.Ser339Ser	synonymous	Exon 9 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.1017G>T	p.Ser339Ser	synonymous	Exon 9 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.1017G>T	p.Ser339Ser	synonymous	Exon 9 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000808 AC: 14 AN: 173222 AF XY: 0.0000758

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: 0.000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000164 AC: 231 AN: 1412646 Hom.: 1 Cov.: 32 AF XY: 0.000172 AC XY: 120 AN XY: 698296

African (AFR) AF: 0.0000310 AC: 1 AN: 32254

American (AMR) AF: 0.00 AC: 0 AN: 37776

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25256

East Asian (EAS) AF: 0.00 AC: 0 AN: 36824

South Asian (SAS) AF: 0.00 AC: 0 AN: 80296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.000206 AC: 224 AN: 1086316

Other (OTH) AF: 0.0000856 AC: 5 AN: 58404

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74370

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000388 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Colorectal cancer, susceptibility to, 10 (2)
-	-	2	not specified (2)
-	-	1	Bile duct cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	POLD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.032
DANN	Benign	0.83
PhyloP100		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs373404887; hg19: chr19-50906356;