rs2230244

Variant names:

• chr19-50403528-C-A
• rs2230244
• NM_002691.4:c.1173C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50403528-C-A
• chr19-50403528-C-G
• chr19-50403528-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001308632.1(POLD1):​c.1173C>A​(p.Asp391Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D391N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLD1 NM_001308632.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.23
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308632.1. 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.1173C>A	p.Asp391Glu	missense	Exon 10 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.1173C>A	p.Asp391Glu	missense	Exon 9 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.1173C>A	p.Asp391Glu	missense	Exon 10 of 27	NP_001243778.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.1173C>A	p.Asp391Glu	missense	Exon 10 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.1173C>A	p.Asp391Glu	missense	Exon 10 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.1173C>A	p.Asp391Glu	missense	Exon 10 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	2.2
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.081	N
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		-2.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.90		Loss of sheet (P = 0.302)
MVP		0.31
MPC		1.6
ClinPred		0.99	D
GERP RS		-6.3
Varity_R		0.96
gMVP		0.94
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230244; hg19: chr19-50906785;