NM_002691.4:c.3120+6_3120+21delAGGGCCGGGAGGTGAG

Variant names:

• chr19-50417093-AGGAGGTGAGAGGGCCG-A
• rs1064792944
• NM_002691.4:c.3120+6_3120+21delAGGGCCGGGAGGTGAG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_002691.4(POLD1):​c.3120+6_3120+21delAGGGCCGGGAGGTGAG variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000071 in 1,407,512 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.83
• 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):

• 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
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• 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

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 19-50417093-AGGAGGTGAGAGGGCCG-A is Benign according to our data. Variant chr19-50417093-AGGAGGTGAGAGGGCCG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407973.

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.3120+6_3120+21delAGGGCCGGGAGGTGAG		splice_region intron	N/A	NP_002682.2
	POLD1	NM_001308632.1		c.3198+6_3198+21delAGGGCCGGGAGGTGAG		splice_region intron	N/A	NP_001295561.1
	POLD1	NM_001256849.1		c.3120+6_3120+21delAGGGCCGGGAGGTGAG		splice_region intron	N/A	NP_001243778.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.3117_3120+12delGGAGGTGAGAGGGCCG	p.Glu1040MetfsTer79	frameshift splice_donor splice_region intron	Exon 25 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.3195_3198+12delGGAGGTGAGAGGGCCG	p.Glu1066MetfsTer79	frameshift splice_donor splice_region intron	Exon 25 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.3117_3120+12delGGAGGTGAGAGGGCCG	p.Glu1040MetfsTer79	frameshift splice_donor splice_region intron	Exon 25 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407512 Hom.: 0 AF XY: 0.00000144 AC XY: 1 AN XY: 695280

African (AFR) AF: 0.00 AC: 0 AN: 32098

American (AMR) AF: 0.00 AC: 0 AN: 36460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 36668

South Asian (SAS) AF: 0.00 AC: 0 AN: 80206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083410

Other (OTH) AF: 0.00 AC: 0 AN: 58304

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer, susceptibility to, 10 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8

Splicing

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

Other links and lift over

dbSNP: rs1064792944; hg19: chr19-50920350;