rs3219362

Variant names:

• chr19-50398595-A-G
• rs3219362
• NM_002691.4:c.-1-256A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-50398595-A-G
• chr19-50398595-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002691.4(POLD1):​c.-1-256A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 133,142 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.017 (46 hom., cov: 30)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.597
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-50398595-A-G is Benign according to our data. Variant chr19-50398595-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1214218.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2276/133142) while in subpopulation NFE AF = 0.026 (1621/62258). AF 95% confidence interval is 0.025. There are 46 homozygotes in GnomAd4. There are 1021 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 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.-1-256A>G		intron	N/A	NP_002682.2	P28340
	POLD1	NM_001256849.1		c.-4-253A>G		intron	N/A	NP_001243778.1	P28340
	POLD1	NM_001438212.1		c.-1-256A>G		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.-1-256A>G		intron	N/A	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.-1-256A>G		intron	N/A	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.-4-253A>G		intron	N/A	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2279 AN: 133084 Hom.: 46 Cov.: 30

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.0310

Gnomad EAS AF: 0.000704

Gnomad SAS AF: 0.00609

Gnomad FIN AF: 0.00316

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0233

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

GnomAD4 genome AF: 0.0171 AC: 2276 AN: 133142 Hom.: 46 Cov.: 30 AF XY: 0.0159 AC XY: 1021 AN XY: 64022

African (AFR) AF: 0.00495 AC: 180 AN: 36328

American (AMR) AF: 0.0210 AC: 272 AN: 12982

Ashkenazi Jewish (ASJ) AF: 0.0310 AC: 99 AN: 3192

East Asian (EAS) AF: 0.000704 AC: 3 AN: 4262

South Asian (SAS) AF: 0.00638 AC: 25 AN: 3918

European-Finnish (FIN) AF: 0.00316 AC: 23 AN: 7268

Middle Eastern (MID) AF: 0.0403 AC: 10 AN: 248

European-Non Finnish (NFE) AF: 0.0260 AC: 1621 AN: 62258

Other (OTH) AF: 0.0231 AC: 43 AN: 1858

Alfa AF: 0.00860 Hom.: 2

Bravo AF: 0.0170

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.63
DANN	Benign	0.32
PhyloP100		-0.60
PromoterAI		0.0044	Neutral
Mutation Taster		=100/0	polymorphism

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: rs3219362; hg19: chr19-50901852;