19-50409679-G-GA

Variant names:

• chr19-50409679-G-GA
• rs3218767
• NM_002691.4:c.2154+13_2154+14insA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002691.4(POLD1):​c.2154+13_2154+14insA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 1,588,032 control chromosomes in the GnomAD database, including 176 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (82 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.12
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 19-50409679-G-GA is Benign according to our data. Variant chr19-50409679-G-GA is described in ClinVar as Benign. ClinVar VariationId is 419831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0638 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.2154+13_2154+14insA		intron	N/A	NP_002682.2
	POLD1	NM_001308632.1		c.2232+13_2232+14insA		intron	N/A	NP_001295561.1
	POLD1	NM_001256849.1		c.2154+13_2154+14insA		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.2154+13_2154+14insA		intron	N/A	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.2232+13_2232+14insA		intron	N/A	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.2154+13_2154+14insA		intron	N/A	ENSP00000473052.1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2900 AN: 152234 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00519 AC: 1214 AN: 234120 AF XY: 0.00372

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.00460

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00185 AC: 2662 AN: 1435680 Hom.: 82 Cov.: 32 AF XY: 0.00159 AC XY: 1127 AN XY: 710336

African (AFR) AF: 0.0638 AC: 2096 AN: 32828

American (AMR) AF: 0.00501 AC: 213 AN: 42534

Ashkenazi Jewish (ASJ) AF: 0.0000797 AC: 2 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39262

South Asian (SAS) AF: 0.000155 AC: 13 AN: 84042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51958

Middle Eastern (MID) AF: 0.00144 AC: 7 AN: 4858

European-Non Finnish (NFE) AF: 0.0000867 AC: 95 AN: 1096066

Other (OTH) AF: 0.00400 AC: 236 AN: 59036

GnomAD4 genome AF: 0.0191 AC: 2906 AN: 152352 Hom.: 94 Cov.: 32 AF XY: 0.0183 AC XY: 1365 AN XY: 74494

African (AFR) AF: 0.0658 AC: 2737 AN: 41584

American (AMR) AF: 0.00777 AC: 119 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00731 Hom.: 5

Bravo AF: 0.0217

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Carcinoma of colon (1)
-	-	1	Colorectal cancer, susceptibility to, 10 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
Mutation Taster		=26/74	disease causing

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: rs3218767; hg19: chr19-50912936;