rs1060501823

Variant names:

• chr19-50402694-C-A
• rs1060501823
• NM_002691.4:c.923C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50402694-C-A
• chr19-50402694-C-G
• chr19-50402694-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002691.4(POLD1):​c.923C>A​(p.Ala308Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,447,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A308V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.34
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

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.923C>A	p.Ala308Glu	missense	Exon 8 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.923C>A	p.Ala308Glu	missense	Exon 7 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.923C>A	p.Ala308Glu	missense	Exon 8 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.923C>A	p.Ala308Glu	missense	Exon 8 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.923C>A	p.Ala308Glu	missense	Exon 8 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.923C>A	p.Ala308Glu	missense	Exon 8 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447018 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 717328

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 43892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39182

South Asian (SAS) AF: 0.00 AC: 0 AN: 85378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4666

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102856

Other (OTH) AF: 0.00 AC: 0 AN: 59516

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		4.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.72		Gain of solvent accessibility (P = 0.0674)
MVP		0.69
MPC		0.81
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.98
gMVP		0.93
Mutation Taster		=24/76	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: rs1060501823; hg19: chr19-50905951;