19-50407153-C-T

Variant names:

• chr19-50407153-C-T
• rs150238541
• NM_002691.4:c.1665C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002691.4(POLD1):​c.1665C>T​(p.Val555Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000979 in 1,607,936 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V555V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -1.54
• Publications: 1 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-50407153-C-T is Benign according to our data. Variant chr19-50407153-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.54 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.1665C>T	p.Val555Val	synonymous	Exon 13 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.1665C>T	p.Val555Val	synonymous	Exon 12 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.1665C>T	p.Val555Val	synonymous	Exon 13 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.1665C>T	p.Val555Val	synonymous	Exon 13 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.1665C>T	p.Val555Val	synonymous	Exon 13 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.1665C>T	p.Val555Val	synonymous	Exon 13 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152162 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000783 AC: 194 AN: 247632 AF XY: 0.000858

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000517

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00102 AC: 1487 AN: 1455658 Hom.: 4 Cov.: 34 AF XY: 0.00107 AC XY: 776 AN XY: 723070

African (AFR) AF: 0.000150 AC: 5 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00177 AC: 152 AN: 86088

European-Finnish (FIN) AF: 0.000512 AC: 27 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00112 AC: 1239 AN: 1107762

Other (OTH) AF: 0.000999 AC: 60 AN: 60038

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152278 Hom.: 0 Cov.: 31 AF XY: 0.000497 AC XY: 37 AN XY: 74456

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68022

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000992 Hom.: 0

Bravo AF: 0.000536

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000890

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	not provided (4)
-	-	2	Colorectal cancer, susceptibility to, 10 (2)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.6
DANN	Benign	0.52
PhyloP100		-1.5
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs150238541; hg19: chr19-50910410;