19-50403179-C-T

Variant names:

• chr19-50403179-C-T
• rs1555790449
• NM_002691.4:c.1097C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002691.4(POLD1):​c.1097C>T​(p.Ala366Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. A366G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.40
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29514778).

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.1097C>T	p.Ala366Val	missense	Exon 9 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.1097C>T	p.Ala366Val	missense	Exon 8 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.1097C>T	p.Ala366Val	missense	Exon 9 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.1097C>T	p.Ala366Val	missense	Exon 9 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.1097C>T	p.Ala366Val	missense	Exon 9 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.1097C>T	p.Ala366Val	missense	Exon 9 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1410416 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 696938

African (AFR) AF: 0.00 AC: 0 AN: 32282

American (AMR) AF: 0.00 AC: 0 AN: 36876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 36930

South Asian (SAS) AF: 0.00 AC: 0 AN: 80184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5438

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085244

Other (OTH) AF: 0.00 AC: 0 AN: 58472

GnomAD4 genome Cov.: 33

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	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.0031
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.87	L
PhyloP100		3.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.064
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.040	B
Vest4		0.41
MutPred		0.48		Gain of sheet (P = 0.0827)
MVP		0.46
MPC		0.72
ClinPred		0.66	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.23
gMVP		0.67
Mutation Taster		=40/60	disease causing

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: rs1555790449; hg19: chr19-50906436;