rs772804822

Variant names:

• chr19-50402110-T-A
• rs772804822
• NM_002691.4:c.575T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50402110-T-A
• chr19-50402110-T-C
• chr19-50402110-T-G

Variant summary

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

The NM_002691.4(POLD1):​c.575T>A​(p.Leu192Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,466 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L192V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16
• 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):

• 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 2 ACMG points.

• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.575T>A	p.Leu192Gln	missense	Exon 5 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.575T>A	p.Leu192Gln	missense	Exon 4 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.575T>A	p.Leu192Gln	missense	Exon 5 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.575T>A	p.Leu192Gln	missense	Exon 5 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.575T>A	p.Leu192Gln	missense	Exon 5 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.575T>A	p.Leu192Gln	missense	Exon 5 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249090 AF XY: 0.00

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460466 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726506

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111260

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer, susceptibility to, 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	0.039
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Polyphen		0.58	P
Vest4		0.55
MutPred		0.53		Gain of disorder (P = 0.0595)
MVP		0.69
MPC		0.63
ClinPred		0.97	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.77
Mutation Taster		=51/49	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

Other links and lift over

dbSNP: rs772804822; hg19: chr19-50905367;