19-50416643-C-G

Variant names:

• chr19-50416643-C-G
• rs918661445
• NM_002691.4:c.2987C>G

Variant summary

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

The NM_002691.4(POLD1):​c.2987C>G​(p.Thr996Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T996M) 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: Not reported in ClinVar
• Conservation: PhyloP100: 4.15
• 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):

• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• 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, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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.2987C>G	p.Thr996Arg	missense	Exon 24 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.3065C>G	p.Thr1022Arg	missense	Exon 23 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2987C>G	p.Thr996Arg	missense	Exon 24 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.2987C>G	p.Thr996Arg	missense	Exon 24 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.3065C>G	p.Thr1022Arg	missense	Exon 24 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2987C>G	p.Thr996Arg	missense	Exon 24 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1413694 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 699996

African (AFR) AF: 0.00 AC: 0 AN: 32322

American (AMR) AF: 0.00 AC: 0 AN: 38492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 37074

South Asian (SAS) AF: 0.00 AC: 0 AN: 80904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5088

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091978

Other (OTH) AF: 0.00 AC: 0 AN: 58672

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.11	T
Polyphen		0.97	D
Vest4		0.47
MutPred		0.49		Gain of MoRF binding (P = 0.0056)
MVP		0.74
MPC		0.87
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.70
gMVP		0.57
Mutation Taster		=29/71	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: rs918661445; hg19: chr19-50919900;