NM_002691.4:c.778A>G

Variant names:

• chr19-50402473-A-G
• rs8105725
• NM_002691.4:c.778A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002691.4(POLD1):​c.778A>G​(p.Ile260Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,612,604 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I260M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (2 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 1.93
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008218169).
• BP6: Variant 19-50402473-A-G is Benign according to our data. Variant chr19-50402473-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221152.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.778A>G	p.Ile260Val	missense	Exon 7 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.778A>G	p.Ile260Val	missense	Exon 6 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.778A>G	p.Ile260Val	missense	Exon 7 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.778A>G	p.Ile260Val	missense	Exon 7 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.778A>G	p.Ile260Val	missense	Exon 7 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.778A>G	p.Ile260Val	missense	Exon 7 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 412 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00936

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000692 AC: 170 AN: 245820 AF XY: 0.000473

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000263 AC: 384 AN: 1460264 Hom.: 2 Cov.: 34 AF XY: 0.000237 AC XY: 172 AN XY: 726316

African (AFR) AF: 0.00963 AC: 322 AN: 33442

American (AMR) AF: 0.000495 AC: 22 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111420

Other (OTH) AF: 0.000481 AC: 29 AN: 60322

GnomAD4 genome AF: 0.00272 AC: 415 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74498

African (AFR) AF: 0.00940 AC: 391 AN: 41582

American (AMR) AF: 0.00118 AC: 18 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000541 Hom.: 0

Bravo AF: 0.00304

ESP6500AA AF: 0.00909 AC: 40

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	3	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Colorectal cancer, susceptibility to, 10 (2)
-	-	1	Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome (1)
-	-	1	Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120 (1)
-	-	1	POLD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.21	N
PhyloP100		1.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.054
Sift	Benign	0.46	T
Sift4G	Benign	0.58	T
Polyphen		0.036	B
Vest4		0.13
MVP		0.50
MPC		0.16
ClinPred		0.011	T
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.052
gMVP		0.47
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8105725; hg19: chr19-50905730;