19-50415803-G-T

Variant names:

• chr19-50415803-G-T
• rs764785216
• NM_002691.4:c.2797G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_002691.4(POLD1):​c.2797G>T​(p.Val933Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,396,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V933A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.68
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25273854).
• BP6: Variant 19-50415803-G-T is Benign according to our data. Variant chr19-50415803-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 469301.

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.2797G>T	p.Val933Leu	missense	Exon 22 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.2875G>T	p.Val959Leu	missense	Exon 21 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2797G>T	p.Val933Leu	missense	Exon 22 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.2797G>T	p.Val933Leu	missense	Exon 22 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.2875G>T	p.Val959Leu	missense	Exon 22 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2797G>T	p.Val933Leu	missense	Exon 22 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000606 AC: 1 AN: 165086 AF XY: 0.0000113

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: 0.0000146

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 26 AN: 1396826 Hom.: 0 Cov.: 33 AF XY: 0.0000218 AC XY: 15 AN XY: 689494

African (AFR) AF: 0.00 AC: 0 AN: 32104

American (AMR) AF: 0.00 AC: 0 AN: 35730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23884

East Asian (EAS) AF: 0.00 AC: 0 AN: 37740

South Asian (SAS) AF: 0.00 AC: 0 AN: 78376

European-Finnish (FIN) AF: 0.0000214 AC: 1 AN: 46668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3964

European-Non Finnish (NFE) AF: 0.0000231 AC: 25 AN: 1080790

Other (OTH) AF: 0.00 AC: 0 AN: 57570

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer, susceptibility to, 10 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Uncertain	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.071
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.17	T
Sift4G	Benign	0.11	T
Polyphen		0.030	B
Vest4		0.37
MutPred		0.48		Loss of catalytic residue at V933 (P = 0.0025)
MVP		0.53
MPC		0.98
ClinPred		0.35	T
GERP RS		2.3
PromoterAI		-0.0060	Neutral
Varity_R		0.18
gMVP		0.38
Mutation Taster		=60/40	polymorphism

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: rs764785216; hg19: chr19-50919060;