rs1143666

Variant names:

• chr19-50402505-T-C
• rs1143666
• NM_002691.4:c.810T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-50402505-T-C
• chr19-50402505-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002691.4(POLD1):​c.810T>C​(p.Ala270Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0243 in 1,609,458 control chromosomes in the GnomAD database, including 6,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A270A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (3263 hom., cov: 33)
  • Exomes 𝑓: 0.015 (2896 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.00
• Publications: 10 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-50402505-T-C is Benign according to our data. Variant chr19-50402505-T-C is described in ClinVar as Benign. ClinVar VariationId is 380227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

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.810T>C	p.Ala270Ala	synonymous	Exon 7 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.810T>C	p.Ala270Ala	synonymous	Exon 6 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.810T>C	p.Ala270Ala	synonymous	Exon 7 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.810T>C	p.Ala270Ala	synonymous	Exon 7 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.810T>C	p.Ala270Ala	synonymous	Exon 7 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.810T>C	p.Ala270Ala	synonymous	Exon 7 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17382 AN: 152008 Hom.: 3238 Cov.: 33

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0520

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00329

Gnomad SAS AF: 0.0470

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.0937

GnomAD2 exomes AF: 0.0340 AC: 8126 AN: 238972 AF XY: 0.0276

Gnomad AFR exome AF: 0.391

Gnomad AMR exome AF: 0.0228

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.00213

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0148 AC: 21613 AN: 1457330 Hom.: 2896 Cov.: 34 AF XY: 0.0141 AC XY: 10251 AN XY: 724678

African (AFR) AF: 0.398 AC: 13264 AN: 33348

American (AMR) AF: 0.0258 AC: 1133 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 631 AN: 25980

East Asian (EAS) AF: 0.00119 AC: 47 AN: 39530

South Asian (SAS) AF: 0.0357 AC: 3046 AN: 85422

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.0306 AC: 176 AN: 5752

European-Non Finnish (NFE) AF: 0.00117 AC: 1297 AN: 1110296

Other (OTH) AF: 0.0336 AC: 2019 AN: 60164

GnomAD4 genome AF: 0.115 AC: 17468 AN: 152128 Hom.: 3263 Cov.: 33 AF XY: 0.112 AC XY: 8299 AN XY: 74398

African (AFR) AF: 0.384 AC: 15955 AN: 41522

American (AMR) AF: 0.0518 AC: 793 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3468

East Asian (EAS) AF: 0.00329 AC: 17 AN: 5162

South Asian (SAS) AF: 0.0472 AC: 228 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 67966

Other (OTH) AF: 0.0974 AC: 206 AN: 2114

Alfa AF: 0.0534 Hom.: 912

Bravo AF: 0.130

Asia WGS AF: 0.0790 AC: 276 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Colorectal cancer, susceptibility to, 10 (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Colorectal cancer, susceptibility to, 10;C3715192:Mandibular hypoplasia-deafness-progeroid syndrome;C5935622:Immunodeficiency 120 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.048
DANN	Benign	0.63
PhyloP100		-4.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs1143666; hg19: chr19-50905762;