rs1555793361

Variant names:

• chr19-50416529-G-A
• rs1555793361
• NM_002691.4:c.2953+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50416529-G-A
• chr19-50416529-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002691.4(POLD1):​c.2953+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000714 in 1,400,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.13
• 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

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2953+1G>A		splice_donor intron	N/A	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.3031+1G>A		splice_donor intron	N/A	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2953+1G>A		splice_donor intron	N/A	NP_001243778.1	P28340

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.2953+1G>A		splice_donor intron	N/A	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.3031+1G>A		splice_donor intron	N/A	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2953+1G>A		splice_donor intron	N/A	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400194 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691416

African (AFR) AF: 0.00 AC: 0 AN: 31838

American (AMR) AF: 0.00 AC: 0 AN: 36386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 36080

South Asian (SAS) AF: 0.00 AC: 0 AN: 79592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082136

Other (OTH) AF: 0.00 AC: 0 AN: 58122

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer, susceptibility to, 10 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Uncertain	0.98
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.1
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -1

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

Other links and lift over

dbSNP: rs1555793361; hg19: chr19-50919786; COSMIC: COSV54529447;