19-50398570-CAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAA

Variant names:

• chr19-50398570-C-CAAA
• rs35689550
• NM_002691.4:c.-1-261_-1-259dupAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002691.4(POLD1):​c.-1-261_-1-259dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0089 (23 hom., cov: 0)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Not reported in ClinVar
• 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: 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00887 (554/62426) while in subpopulation AFR AF = 0.0199 (285/14334). AF 95% confidence interval is 0.018. There are 23 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.-1-261_-1-259dupAAA		intron	N/A	NP_002682.2	P28340
	POLD1	NM_001256849.1		c.-4-258_-4-256dupAAA		intron	N/A	NP_001243778.1	P28340
	POLD1	NM_001438212.1		c.-1-261_-1-259dupAAA		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_-1-280insAAA		intron	N/A	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.-1-281_-1-280insAAA		intron	N/A	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.-4-278_-4-277insAAA		intron	N/A	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.00886 AC: 553 AN: 62404 Hom.: 23 Cov.: 0

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00772

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00763

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.00575

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00430

Gnomad OTH AF: 0.00838

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

GnomAD4 genome AF: 0.00887 AC: 554 AN: 62426 Hom.: 23 Cov.: 0 AF XY: 0.00992 AC XY: 263 AN XY: 26508

African (AFR) AF: 0.0199 AC: 285 AN: 14334

American (AMR) AF: 0.0122 AC: 49 AN: 4014

Ashkenazi Jewish (ASJ) AF: 0.00763 AC: 16 AN: 2098

East Asian (EAS) AF: 0.0155 AC: 26 AN: 1682

South Asian (SAS) AF: 0.00578 AC: 6 AN: 1038

European-Finnish (FIN) AF: 0.00198 AC: 1 AN: 506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 58

European-Non Finnish (NFE) AF: 0.00430 AC: 161 AN: 37462

Other (OTH) AF: 0.00838 AC: 6 AN: 716

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

Other links and lift over

dbSNP: rs35689550; hg19: chr19-50901827;