rs3219433

chr19-50415712-A-Cchr19-50415712-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002691.4(POLD1):c.2718-12A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0087 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.90

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS2: High AC in GnomAdExome at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.2718-12A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.2718-12A>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002691.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 533 AN: 61056 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.0145

Gnomad AMR AF: 0.00830

Gnomad ASJ AF: 0.00781

Gnomad EAS AF: 0.00226

Gnomad SAS AF: 0.00341

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00794

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.00358

GnomAD3 exomes AF: 0.000169 AC: 20 AN: 118132 Hom.: 0 AF XY: 0.000155 AC XY: 10 AN XY: 64506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000500

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.000361

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000221

Gnomad OTH exome AF: 0.000595

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000323 AC: 29 AN: 896936 Hom.: 0 Cov.: 30 AF XY: 0.0000246 AC XY: 11 AN XY: 446350

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000363

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000619

Gnomad4 FIN exome AF: 0.000108

Gnomad4 NFE exome AF: 0.0000322

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00871 AC: 533 AN: 61182 Hom.: 0 Cov.: 0 AF XY: 0.00824 AC XY: 246 AN XY: 29842

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.00781

Gnomad4 EAS AF: 0.00225

Gnomad4 SAS AF: 0.00341

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.0208

Gnomad4 OTH AF: 0.00350

Alfa AF: 0.000222 Hom.: 376

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2015

The c.2718-12A>C intronic alteration consists of a A to C substitution 12 nucleotides before coding exon 21 in the POLD1 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.40
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs3219433; hg19: chr19-50918969;