19-50398931-A-T

Variant names:

• chr19-50398931-A-T
• rs150066950
• NM_002691.4:c.80A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002691.4(POLD1):​c.80A>T​(p.Asp27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,595,608 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. D27G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (4 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:16
• Conservation: PhyloP100: 1.10
• Publications: 7 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037871003).
• BP6: Variant 19-50398931-A-T is Benign according to our data. Variant chr19-50398931-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245862.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.80A>T	p.Asp27Val	missense	Exon 2 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.80A>T	p.Asp27Val	missense	Exon 1 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.80A>T	p.Asp27Val	missense	Exon 2 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.80A>T	p.Asp27Val	missense	Exon 2 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.80A>T	p.Asp27Val	missense	Exon 2 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.80A>T	p.Asp27Val	missense	Exon 2 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00301

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00198 AC: 435 AN: 220036 AF XY: 0.00194

Gnomad AFR exome AF: 0.000440

Gnomad AMR exome AF: 0.000717

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000577

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00270 AC: 3903 AN: 1443270 Hom.: 4 Cov.: 33 AF XY: 0.00260 AC XY: 1862 AN XY: 716064

African (AFR) AF: 0.000361 AC: 12 AN: 33270

American (AMR) AF: 0.000600 AC: 25 AN: 41700

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 81 AN: 25590

East Asian (EAS) AF: 0.00 AC: 0 AN: 39150

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83202

European-Finnish (FIN) AF: 0.00109 AC: 57 AN: 52112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4258

European-Non Finnish (NFE) AF: 0.00328 AC: 3621 AN: 1104344

Other (OTH) AF: 0.00178 AC: 106 AN: 59644

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74500

African (AFR) AF: 0.000433 AC: 18 AN: 41576

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00301 AC: 205 AN: 68032

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00258 Hom.: 1

Bravo AF: 0.00181

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00214 AC: 259

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	2	4	not specified (6)
-	-	3	Colorectal cancer, susceptibility to, 10 (3)
-	1	2	Hereditary cancer-predisposing syndrome (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	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.060
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.036	D
Polyphen		0.028	B
Vest4		0.24
MVP		0.52
MPC		0.35
ClinPred		0.029	T
GERP RS		3.3
PromoterAI		0.0040	Neutral
Varity_R		0.17
gMVP		0.36
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150066950; hg19: chr19-50902188;