chr19-50415795-C-T

Variant names:

• chr19-50415795-C-T
• rs1060501855
• NM_002691.4:c.2789C>T

Variant summary

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

The NM_002691.4(POLD1):​c.2789C>T​(p.Ala930Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,409,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A930G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.49
• Publications: 1 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, Orphanet
• 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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.2789C>T	p.Ala930Val	missense	Exon 22 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.2867C>T	p.Ala956Val	missense	Exon 21 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2789C>T	p.Ala930Val	missense	Exon 22 of 27	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.2789C>T	p.Ala930Val	missense	Exon 22 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.2867C>T	p.Ala956Val	missense	Exon 22 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2789C>T	p.Ala930Val	missense	Exon 22 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1409684 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 696974

African (AFR) AF: 0.00 AC: 0 AN: 32586

American (AMR) AF: 0.00 AC: 0 AN: 37802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24472

East Asian (EAS) AF: 0.00 AC: 0 AN: 38042

South Asian (SAS) AF: 0.00 AC: 0 AN: 79652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4028

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1087618

Other (OTH) AF: 0.00 AC: 0 AN: 58176

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.036
Eigen_PC	Benign	0.030
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.15
Sift	Benign	0.033	D
Sift4G	Benign	0.067	T
Polyphen		0.11	B
Vest4		0.44
MutPred		0.64		Gain of methylation at K931 (P = 0.055)
MVP		0.53
MPC		0.77
ClinPred		0.98	D
GERP RS		3.3
PromoterAI		-0.0044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.51
gMVP		0.42
Mutation Taster		=23/77	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: rs1060501855; hg19: chr19-50919052;