19-50402067-G-C

Variant names:

• chr19-50402067-G-C
• rs140707092
• NM_002691.4:c.532G>C

Variant summary

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

The NM_002691.4(POLD1):​c.532G>C​(p.Gly178Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,614,034 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G178W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (1 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 3.05
• Publications: 8 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09199464).

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.532G>C	p.Gly178Arg	missense	Exon 5 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.532G>C	p.Gly178Arg	missense	Exon 4 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.532G>C	p.Gly178Arg	missense	Exon 5 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.532G>C	p.Gly178Arg	missense	Exon 5 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.532G>C	p.Gly178Arg	missense	Exon 5 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.532G>C	p.Gly178Arg	missense	Exon 5 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000798 AC: 20 AN: 250686 AF XY: 0.0000737

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461744 Hom.: 1 Cov.: 34 AF XY: 0.0000275 AC XY: 20 AN XY: 727196

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.000224 AC: 10 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111956

Other (OTH) AF: 0.0000662 AC: 4 AN: 60386

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74470

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

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	-	POLD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	N
PhyloP100		3.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.058
Sift	Benign	0.28	T
Sift4G	Benign	0.25	T
Polyphen		0.11	B
Vest4		0.32
MutPred		0.59		Gain of MoRF binding (P = 0.0187)
MVP		0.43
MPC		0.73
ClinPred		0.043	T
GERP RS		3.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.074
gMVP		0.50
Mutation Taster		=8/89	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: rs140707092; hg19: chr19-50905324;