rs140379348

Variant names:

• chr19-50407005-G-A
• rs140379348
• NM_002691.4:c.1517G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50407005-G-A
• chr19-50407005-G-C
• chr19-50407005-G-T

Variant summary

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

The NM_002691.4(POLD1):​c.1517G>A​(p.Arg506His) variant causes a missense change. The variant allele was found at a frequency of 0.0000191 in 1,415,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R506C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 6.05
• Publications: 16 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: Uncertain_significance. The variant received 0 ACMG points.

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.1517G>A	p.Arg506His	missense	Exon 13 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.1517G>A	p.Arg506His	missense	Exon 12 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.1517G>A	p.Arg506His	missense	Exon 13 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.1517G>A	p.Arg506His	missense	Exon 13 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.1517G>A	p.Arg506His	missense	Exon 13 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.1517G>A	p.Arg506His	missense	Exon 13 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.0000208 AC: 3 AN: 144186 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000512

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000815 AC: 2 AN: 245380 AF XY: 0.00000752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000189 AC: 24 AN: 1271338 Hom.: 0 Cov.: 34 AF XY: 0.0000159 AC XY: 10 AN XY: 630384

African (AFR) AF: 0.00 AC: 0 AN: 28930

American (AMR) AF: 0.00 AC: 0 AN: 38548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18658

East Asian (EAS) AF: 0.0000857 AC: 2 AN: 23334

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83724

European-Finnish (FIN) AF: 0.0000273 AC: 1 AN: 36602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4580

European-Non Finnish (NFE) AF: 0.0000182 AC: 18 AN: 989272

Other (OTH) AF: 0.0000210 AC: 1 AN: 47690

GnomAD4 genome AF: 0.0000208 AC: 3 AN: 144186 Hom.: 0 Cov.: 30 AF XY: 0.0000143 AC XY: 1 AN XY: 70080

African (AFR) AF: 0.0000512 AC: 2 AN: 39074

American (AMR) AF: 0.00 AC: 0 AN: 14384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.00 AC: 0 AN: 4362

South Asian (SAS) AF: 0.00 AC: 0 AN: 4082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66338

Other (OTH) AF: 0.00 AC: 0 AN: 2012

Alfa AF: 0.0000681 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.18
Sift	Benign	0.062	T
Sift4G	Benign	0.080	T
Polyphen		0.76	P
Vest4		0.66
MVP		0.53
MPC		1.8
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.65
gMVP		0.74
Mutation Taster		=34/66	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: rs140379348; hg19: chr19-50910262; COSMIC: COSV70954032;