chr19-50399029-T-G

Variant names:

• chr19-50399029-T-G
• rs1555789135
• NM_002691.4:c.178T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002691.4(POLD1):​c.178T>G​(p.Ser60Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. S60P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03485939).

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.178T>G	p.Ser60Ala	missense	Exon 2 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.178T>G	p.Ser60Ala	missense	Exon 1 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.178T>G	p.Ser60Ala	missense	Exon 2 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.178T>G	p.Ser60Ala	missense	Exon 2 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.178T>G	p.Ser60Ala	missense	Exon 2 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.178T>G	p.Ser60Ala	missense	Exon 2 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404312 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 693066

African (AFR) AF: 0.00 AC: 0 AN: 32068

American (AMR) AF: 0.00 AC: 0 AN: 36022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 36580

South Asian (SAS) AF: 0.00 AC: 0 AN: 79620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4884

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1081862

Other (OTH) AF: 0.00 AC: 0 AN: 58270

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.20
DANN	Benign	0.79
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.74
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.023
Sift	Benign	0.76	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.082
MutPred		0.24		Loss of phosphorylation at S60 (P = 0.0276)
MVP		0.25
MPC		0.15
ClinPred		0.059	T
GERP RS		-6.6
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.015
gMVP		0.14
Mutation Taster		=97/3	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: rs1555789135; hg19: chr19-50902286;