19-50416682-G-A

Variant names:

• chr19-50416682-G-A
• rs757190258
• NM_002691.4:c.3026G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002691.4(POLD1):​c.3026G>A​(p.Arg1009His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,399,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1009C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.32
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22438613).

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.3026G>A	p.Arg1009His	missense	Exon 24 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.3104G>A	p.Arg1035His	missense	Exon 23 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.3026G>A	p.Arg1009His	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.3026G>A	p.Arg1009His	missense	Exon 24 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.3104G>A	p.Arg1035His	missense	Exon 24 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.3026G>A	p.Arg1009His	missense	Exon 24 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000334 AC: 5 AN: 149668 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000837

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000200 AC: 28 AN: 1399418 Hom.: 0 Cov.: 34 AF XY: 0.0000188 AC XY: 13 AN XY: 691792

African (AFR) AF: 0.00 AC: 0 AN: 31900

American (AMR) AF: 0.00 AC: 0 AN: 36876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 36300

South Asian (SAS) AF: 0.00 AC: 0 AN: 79864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4554

European-Non Finnish (NFE) AF: 0.0000249 AC: 27 AN: 1085200

Other (OTH) AF: 0.0000172 AC: 1 AN: 58222

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000178 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Colorectal cancer, susceptibility to, 10 (1)
-	1	-	Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.3
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.16
Sift	Benign	0.047	D
Sift4G	Uncertain	0.053	T
Polyphen		0.91	P
Vest4		0.25
MutPred		0.68		Loss of MoRF binding (P = 0.0377)
MVP		0.49
MPC		0.78
ClinPred		0.52	D
GERP RS		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.56
gMVP		0.40
Mutation Taster		=68/32	polymorphism

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: rs757190258; hg19: chr19-50919939;