19-50417844-G-T

Variant names:

• chr19-50417844-G-T
• rs541931950
• NM_002691.4:c.3221G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002691.4(POLD1):​c.3221G>T​(p.Arg1074Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000692 in 1,445,492 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. R1074G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 38 uncertain in NM_002691.4
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.3221G>T	p.Arg1074Leu	missense splice_region	Exon 27 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.3299G>T	p.Arg1100Leu	missense splice_region	Exon 26 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.3221G>T	p.Arg1074Leu	missense splice_region	Exon 27 of 27	NP_001243778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.3221G>T	p.Arg1074Leu	missense splice_region	Exon 27 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.3299G>T	p.Arg1100Leu	missense splice_region	Exon 27 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.3221G>T	p.Arg1074Leu	missense splice_region	Exon 27 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445492 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718040

⚠️ 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: 32328

American (AMR) AF: 0.0000232 AC: 1 AN: 43138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.00 AC: 0 AN: 39104

South Asian (SAS) AF: 0.00 AC: 0 AN: 84040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103994

Other (OTH) AF: 0.00 AC: 0 AN: 59652

⚠️ 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.45
MutPred		0.58		Loss of phosphorylation at T1072 (P = 0.0534)
MVP		0.75
MPC		1.2
ClinPred		0.98	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.74
Mutation Taster		=38/62	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: rs541931950; hg19: chr19-50921101;