19-50415542-C-G

Variant names:

• chr19-50415542-C-G
• rs146344351
• NM_002691.4:c.2669C>G

Variant summary

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

The NM_002691.4(POLD1):​c.2669C>G​(p.Ala890Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. A890V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28529507).

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.2669C>G	p.Ala890Gly	missense	Exon 21 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.2747C>G	p.Ala916Gly	missense	Exon 20 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.2669C>G	p.Ala890Gly	missense	Exon 21 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.2669C>G	p.Ala890Gly	missense	Exon 21 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.2747C>G	p.Ala916Gly	missense	Exon 21 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.2669C>G	p.Ala890Gly	missense	Exon 21 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460560 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726560

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111644

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.82	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.0030	B
Vest4		0.20
MutPred		0.44		Loss of stability (P = 0.0404)
MVP		0.46
MPC		1.1
ClinPred		0.75	D
GERP RS		4.3
PromoterAI		-0.036	Neutral
Varity_R		0.098
gMVP		0.46
Mutation Taster		=70/30	polymorphism

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: rs146344351; hg19: chr19-50918799;