19-50415816-T-C

Variant names:

• chr19-50415816-T-C
• rs1011628932
• NM_002691.4:c.2810T>C

Variant summary

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

The NM_002691.4(POLD1):​c.2810T>C​(p.Met937Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,318 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict 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. M937K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• 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):

• 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
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.2810T>C	p.Met937Thr	missense_variant	Exon 22 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.2810T>C	p.Met937Thr	missense_variant	Exon 22 of 27	1	NM_002691.4	ENSP00000406046.1
ENSG00000142539	ENST00000599632.1	c.17T>C	p.Met6Thr	missense_variant	Exon 1 of 10	5		ENSP00000473233.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377318 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 677650

⚠️ 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: 31566

American (AMR) AF: 0.00 AC: 0 AN: 33776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23056

East Asian (EAS) AF: 0.00 AC: 0 AN: 37098

South Asian (SAS) AF: 0.00 AC: 0 AN: 76166

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3908

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069610

Other (OTH) AF: 0.00 AC: 0 AN: 56676

⚠️ 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.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M937T variant (also known as c.2810T>C), located in coding exon 21 of the POLD1 gene, results from a T to C substitution at nucleotide position 2810. The methionine at codon 937 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.0079	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T;.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.053
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L;.;.;L
PhyloP100		3.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.0	N;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.047	D;.;.;.
Sift4G	Uncertain	0.054	T;T;T;T
Polyphen		0.0060	B;.;.;B
Vest4		0.83
MutPred		0.39		Loss of stability (P = 0.133);.;.;Loss of stability (P = 0.133);
MVP		0.44
MPC		0.85
ClinPred		0.74	D
GERP RS		3.3
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.52
gMVP		0.50
Mutation Taster		=47/53	disease causing

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: rs1011628932; hg19: chr19-50919073; COSMIC: COSV54529813;