rs3217943

Variant names:

• chr7-44124492-T-C
• rs3217943
• ENST00000433715.6:c.-239A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000433715.6(POLD2):​c.-239A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,092 control chromosomes in the GnomAD database, including 3,725 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3724 hom., cov: 31)
  • Exomes 𝑓: 0.25 (1 hom.)
• Consequence: POLD2 ENST00000433715.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.425
• Publications: 5 publications found

Genes affected

POLD2 (HGNC:9176): (DNA polymerase delta 2, accessory subunit) This gene encodes the 50-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. The encoded protein is required for the stimulation of DNA polymerase delta activity by the processivity cofactor proliferating cell nuclear antigen (PCNA). Expression of this gene may be a marker for ovarian carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 5. [provided by RefSeq, Mar 2012]

POLD2 Gene-Disease associations (from GenCC):

• non-severe combined immunodeficiency due to polymerase delta deficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD2	XM_047420500.1	c.-239A>G		upstream_gene_variant			XP_047276456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD2	ENST00000433715.6	c.-239A>G		upstream_gene_variant		3		ENSP00000389816.2

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31382 AN: 151962 Hom.: 3721 Cov.: 31

Gnomad AFR AF: 0.0885

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.250

GnomAD4 exome AF: 0.250 AC: 3 AN: 12 Hom.: 1 AF XY: 0.300 AC XY: 3 AN XY: 10

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.300 AC: 3 AN: 10

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.206 AC: 31391 AN: 152080 Hom.: 3724 Cov.: 31 AF XY: 0.202 AC XY: 15056 AN XY: 74352

African (AFR) AF: 0.0884 AC: 3670 AN: 41498

American (AMR) AF: 0.283 AC: 4329 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3470

East Asian (EAS) AF: 0.233 AC: 1202 AN: 5158

South Asian (SAS) AF: 0.101 AC: 485 AN: 4818

European-Finnish (FIN) AF: 0.198 AC: 2100 AN: 10580

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17758 AN: 67966

Other (OTH) AF: 0.250 AC: 526 AN: 2108

Alfa AF: 0.214 Hom.: 467

Bravo AF: 0.212

Asia WGS AF: 0.159 AC: 555 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.6
DANN	Benign	0.73
PhyloP100		0.42
PromoterAI		0.015	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3217943; hg19: chr7-44164091;