19-50398570-C-CAA

Variant names:

• chr19-50398570-C-CAA
• rs35689550
• NM_002691.4:c.-1-260_-1-259dupAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002691.4(POLD1):​c.-1-260_-1-259dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.082 (768 hom., cov: 0)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.527
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• 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
• 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 -10 ACMG points.

• BP6: Variant 19-50398570-C-CAA is Benign according to our data. Variant chr19-50398570-C-CAA is described in ClinVar as Benign. ClinVar VariationId is 1302817.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.14 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.-1-260_-1-259dupAA		intron	N/A	NP_002682.2	P28340
	POLD1	NM_001256849.1		c.-4-257_-4-256dupAA		intron	N/A	NP_001243778.1	P28340
	POLD1	NM_001438212.1		c.-1-260_-1-259dupAA		intron	N/A	NP_001425141.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.-1-281_-1-280insAA		intron	N/A	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.-1-281_-1-280insAA		intron	N/A	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.-4-278_-4-277insAA		intron	N/A	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 5185 AN: 63032 Hom.: 768 Cov.: 0

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0639

Gnomad ASJ AF: 0.0883

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.0714

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0861

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0823 AC: 5188 AN: 63052 Hom.: 768 Cov.: 0 AF XY: 0.0833 AC XY: 2233 AN XY: 26800

African (AFR) AF: 0.145 AC: 2099 AN: 14432

American (AMR) AF: 0.0639 AC: 259 AN: 4052

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 185 AN: 2094

East Asian (EAS) AF: 0.110 AC: 186 AN: 1690

South Asian (SAS) AF: 0.106 AC: 111 AN: 1044

European-Finnish (FIN) AF: 0.0198 AC: 10 AN: 506

Middle Eastern (MID) AF: 0.0714 AC: 4 AN: 56

European-Non Finnish (NFE) AF: 0.0581 AC: 2203 AN: 37922

Other (OTH) AF: 0.0847 AC: 62 AN: 732

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs35689550; hg19: chr19-50901827;