19-50398963-C-A

Variant names:

• chr19-50398963-C-A
• rs1484596172
• NM_002691.4:c.112C>A
• POLD1 p.Leu38Met

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002691.4(POLD1):​c.112C>A​(p.Leu38Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L38Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20876774).

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.112C>A	p.Leu38Met	missense	Exon 2 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.112C>A	p.Leu38Met	missense	Exon 1 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.112C>A	p.Leu38Met	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.112C>A	p.Leu38Met	missense	Exon 2 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.112C>A	p.Leu38Met	missense	Exon 2 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.112C>A	p.Leu38Met	missense	Exon 2 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429338 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 707648

⚠️ 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: 33076

American (AMR) AF: 0.0000257 AC: 1 AN: 38936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25416

East Asian (EAS) AF: 0.00 AC: 0 AN: 38660

South Asian (SAS) AF: 0.00 AC: 0 AN: 81706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096302

Other (OTH) AF: 0.00 AC: 0 AN: 59194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.10
Sift	Benign	0.039	D
Sift4G	Benign	0.086	T
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.41
Mutation Taster		=84/16	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1484596172;

hg19: chr19-50902220;