rs3218775

Variant names:

• chr19-50414972-G-A
• rs3218775
• NM_002691.4:c.2546G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50414972-G-A
• chr19-50414972-G-T
• chr19-50414972-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002691.4(POLD1):​c.2546G>A​(p.Arg849His) variant causes a missense change. The variant allele was found at a frequency of 0.00734 in 1,590,186 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R849C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (65 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 3.81
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074485242).
• BP6: Variant 19-50414972-G-A is Benign according to our data. Variant chr19-50414972-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00742 (10666/1437878) while in subpopulation MID AF = 0.0189 (108/5706). AF 95% confidence interval is 0.016. There are 65 homozygotes in GnomAdExome4. There are 5256 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.2546G>A	p.Arg849His	missense	Exon 20 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.2624G>A	p.Arg875His	missense	Exon 19 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2546G>A	p.Arg849His	missense	Exon 20 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.2546G>A	p.Arg849His	missense	Exon 20 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.2624G>A	p.Arg875His	missense	Exon 20 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2546G>A	p.Arg849His	missense	Exon 20 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1014 AN: 152190 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00783 AC: 1714 AN: 218902 AF XY: 0.00796

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.00688

Gnomad ASJ exome AF: 0.0419

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00778

Gnomad NFE exome AF: 0.00890

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00742 AC: 10666 AN: 1437878 Hom.: 65 Cov.: 32 AF XY: 0.00736 AC XY: 5256 AN XY: 713736

African (AFR) AF: 0.00119 AC: 39 AN: 32814

American (AMR) AF: 0.00770 AC: 323 AN: 41956

Ashkenazi Jewish (ASJ) AF: 0.0436 AC: 1103 AN: 25312

East Asian (EAS) AF: 0.0000519 AC: 2 AN: 38530

South Asian (SAS) AF: 0.00177 AC: 149 AN: 83992

European-Finnish (FIN) AF: 0.00735 AC: 375 AN: 51010

Middle Eastern (MID) AF: 0.0189 AC: 108 AN: 5706

European-Non Finnish (NFE) AF: 0.00732 AC: 8047 AN: 1099290

Other (OTH) AF: 0.00877 AC: 520 AN: 59268

GnomAD4 genome AF: 0.00664 AC: 1012 AN: 152308 Hom.: 10 Cov.: 33 AF XY: 0.00650 AC XY: 484 AN XY: 74476

African (AFR) AF: 0.00140 AC: 58 AN: 41562

American (AMR) AF: 0.0101 AC: 155 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0446 AC: 155 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.00555 AC: 59 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00769 AC: 523 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2112

Alfa AF: 0.00782 Hom.: 19

Bravo AF: 0.00685

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00672 AC: 814

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	Colorectal cancer, susceptibility to, 10 (3)
-	-	1	Carcinoma of colon (1)
-	-	1	Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L
PhyloP100		3.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.052
Sift	Benign	0.36	T
Sift4G	Benign	0.41	T
Polyphen		0.025	B
Vest4		0.17
MVP		0.48
MPC		0.78
ClinPred		0.0068	T
GERP RS		3.5
Varity_R		0.061
gMVP		0.38
Mutation Taster		=93/7	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: rs3218775; hg19: chr19-50918229;