NM_002691.4:c.3170A>G

Variant names:

• chr19-50417221-A-G
• rs768747132
• NM_002691.4:c.3170A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002691.4(POLD1):​c.3170A>G​(p.Gln1057Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,454,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. Q1057H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.05
• Publications: 1 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

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

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.3170A>G	p.Gln1057Arg	missense	Exon 26 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.3248A>G	p.Gln1083Arg	missense	Exon 25 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.3170A>G	p.Gln1057Arg	missense	Exon 26 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.3170A>G	p.Gln1057Arg	missense	Exon 26 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.3248A>G	p.Gln1083Arg	missense	Exon 26 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.3170A>G	p.Gln1057Arg	missense	Exon 26 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238142 AF XY: 0.00000768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000918

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454002 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 723170

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110352

Other (OTH) AF: 0.00 AC: 0 AN: 60166

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.0027	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.54	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.65	P
Vest4		0.71
MutPred		0.49		Gain of MoRF binding (P = 0.0119)
MVP		0.62
MPC		1.7
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.95
gMVP		0.79
Mutation Taster		=44/56	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: rs768747132; hg19: chr19-50920478;