chr19-50415794-G-C

Variant names:

• chr19-50415794-G-C
• rs144111108
• NM_002691.4:c.2788G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002691.4(POLD1):​c.2788G>C​(p.Ala930Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,408,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A930V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.09
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36369672).

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.2788G>C	p.Ala930Pro	missense	Exon 22 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.2866G>C	p.Ala956Pro	missense	Exon 21 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.2788G>C	p.Ala930Pro	missense	Exon 22 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.2788G>C	p.Ala930Pro	missense	Exon 22 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.2866G>C	p.Ala956Pro	missense	Exon 22 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.2788G>C	p.Ala930Pro	missense	Exon 22 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408668 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 696490

African (AFR) AF: 0.00 AC: 0 AN: 32528

American (AMR) AF: 0.00 AC: 0 AN: 37628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24462

East Asian (EAS) AF: 0.00 AC: 0 AN: 38024

South Asian (SAS) AF: 0.00 AC: 0 AN: 79564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4018

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087212

Other (OTH) AF: 0.00 AC: 0 AN: 58120

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.15
Sift	Benign	0.088	T
Sift4G	Benign	0.13	T
Polyphen		0.030	B
Vest4		0.45
MutPred		0.63		Loss of stability (P = 0.0208)
MVP		0.55
MPC		0.85
ClinPred		0.86	D
GERP RS		3.3
PromoterAI		-0.031	Neutral
Varity_R		0.89
gMVP		0.62
Mutation Taster		=35/65	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: rs144111108; hg19: chr19-50919051;