NM_002691.4:c.849G>T

Variant names:

• chr19-50402620-G-T
• rs113282414
• NM_002691.4:c.849G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002691.4(POLD1):​c.849G>T​(p.Gln283His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,573,394 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict 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. Q283R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.976
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 19-50402620-G-T is Benign according to our data. Variant chr19-50402620-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1532/152378) while in subpopulation AFR AF = 0.0349 (1453/41592). AF 95% confidence interval is 0.0334. There are 22 homozygotes in GnomAd4. There are 758 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 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.849G>T	p.Gln283His	missense	Exon 8 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.849G>T	p.Gln283His	missense	Exon 7 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.849G>T	p.Gln283His	missense	Exon 8 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.849G>T	p.Gln283His	missense	Exon 8 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.849G>T	p.Gln283His	missense	Exon 8 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.849G>T	p.Gln283His	missense	Exon 8 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.00994 AC: 1514 AN: 152260 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00267 AC: 499 AN: 187218 AF XY: 0.00214

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000760

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000995 AC: 1414 AN: 1421016 Hom.: 18 Cov.: 34 AF XY: 0.000878 AC XY: 617 AN XY: 702946

African (AFR) AF: 0.0357 AC: 1170 AN: 32806

American (AMR) AF: 0.00229 AC: 87 AN: 37926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 37874

South Asian (SAS) AF: 0.0000852 AC: 7 AN: 82130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50322

Middle Eastern (MID) AF: 0.00119 AC: 6 AN: 5052

European-Non Finnish (NFE) AF: 0.0000275 AC: 30 AN: 1090780

Other (OTH) AF: 0.00194 AC: 114 AN: 58796

GnomAD4 genome AF: 0.0101 AC: 1532 AN: 152378 Hom.: 22 Cov.: 33 AF XY: 0.0102 AC XY: 758 AN XY: 74514

African (AFR) AF: 0.0349 AC: 1453 AN: 41592

American (AMR) AF: 0.00359 AC: 55 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00241 Hom.: 6

Bravo AF: 0.0116

ESP6500AA AF: 0.0324 AC: 142

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00252 AC: 303

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Colorectal cancer, susceptibility to, 10 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Polymerase proofreading-related adenomatous polyposis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	17
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.98
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.059
Sift	Benign	0.29	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.42		Loss of ubiquitination at K280 (P = 0.1055)
MVP		0.36
MPC		0.18
ClinPred		0.0037	T
GERP RS		2.1
Varity_R		0.094
gMVP		0.50
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113282414; hg19: chr19-50905877; COSMIC: COSV70953898; COSMIC: COSV70953898;