rs569987101

Variant names:

• chr19-50417249-C-A
• rs569987101
• NM_002691.4:c.3198C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50417249-C-A
• chr19-50417249-C-G
• chr19-50417249-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002691.4(POLD1):​c.3198C>A​(p.His1066Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1066R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.93
• 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):

• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 29 uncertain in NM_002691.4
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.3198C>A	p.His1066Gln	missense	Exon 26 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.3276C>A	p.His1092Gln	missense	Exon 25 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.3198C>A	p.His1066Gln	missense	Exon 26 of 27	NP_001243778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.3198C>A	p.His1066Gln	missense	Exon 26 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.3276C>A	p.His1092Gln	missense	Exon 26 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.3198C>A	p.His1066Gln	missense	Exon 26 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447028 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 719422

African (AFR) AF: 0.00 AC: 0 AN: 33288

American (AMR) AF: 0.00 AC: 0 AN: 44062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39372

South Asian (SAS) AF: 0.00 AC: 0 AN: 85138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107988

Other (OTH) AF: 0.00 AC: 0 AN: 59978

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.4
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		-1.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Benign	0.23
Sift	Benign	0.031	D
Sift4G	Uncertain	0.043	D
Polyphen		0.82	P
Vest4		0.68
MutPred		0.37		Loss of catalytic residue at H1066 (P = 0.0245)
MVP		0.48
MPC		1.6
ClinPred		0.99	D
GERP RS		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.65
Mutation Taster		=31/69	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: rs569987101; hg19: chr19-50920506;