rs137953986

Variant names:

• chr19-50401894-G-A
• rs137953986
• NM_002691.4:c.433G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50401894-G-A
• chr19-50401894-G-C
• chr19-50401894-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002691.4(POLD1):​c.433G>A​(p.Ala145Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,613,944 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: POLD1 NM_002691.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 3.72
• Publications: 11 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011245161).
• BP6: Variant 19-50401894-G-A is Benign according to our data. Variant chr19-50401894-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

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.433G>A	p.Ala145Thr	missense	Exon 4 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.433G>A	p.Ala145Thr	missense	Exon 3 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.433G>A	p.Ala145Thr	missense	Exon 4 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.433G>A	p.Ala145Thr	missense	Exon 4 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.433G>A	p.Ala145Thr	missense	Exon 4 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.433G>A	p.Ala145Thr	missense	Exon 4 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152038 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00268 AC: 674 AN: 251270 AF XY: 0.00264

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00271 AC: 3967 AN: 1461788 Hom.: 6 Cov.: 35 AF XY: 0.00268 AC XY: 1948 AN XY: 727218

African (AFR) AF: 0.000239 AC: 8 AN: 33474

American (AMR) AF: 0.000335 AC: 15 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00194 AC: 167 AN: 86256

European-Finnish (FIN) AF: 0.0117 AC: 626 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00270 AC: 3007 AN: 1111964

Other (OTH) AF: 0.00233 AC: 141 AN: 60390

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152156 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74382

African (AFR) AF: 0.000457 AC: 19 AN: 41532

American (AMR) AF: 0.00150 AC: 23 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4814

European-Finnish (FIN) AF: 0.0126 AC: 134 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00265 AC: 180 AN: 67974

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00152

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00254 AC: 308

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00172

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Colorectal cancer, susceptibility to, 10 (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Colon cancer (1)
-	-	1	Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome (1)
-	-	1	Familial ovarian cancer (1)
-	-	1	POLD1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.48	N
PhyloP100		3.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.096
Sift	Benign	0.61	T
Sift4G	Benign	0.73	T
Polyphen		0.068	B
Vest4		0.52
MVP		0.43
MPC		0.20
ClinPred		0.0094	T
GERP RS		4.0
Varity_R		0.10
gMVP		0.38
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137953986; hg19: chr19-50905151;