19-50416437-G-C

Variant names:

• chr19-50416437-G-C
• rs3219440
• NM_002691.4:c.2862G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002691.4(POLD1):​c.2862G>C​(p.Thr954Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,549,980 control chromosomes in the GnomAD database, including 42 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. T954T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (22 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.99
• Publications: 4 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

ENSG00000142539 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.035).
• BP6: Variant 19-50416437-G-C is Benign according to our data. Variant chr19-50416437-G-C is described in ClinVar as Benign. ClinVar VariationId is 221052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1544/152304) while in subpopulation AFR AF = 0.0347 (1442/41556). AF 95% confidence interval is 0.0332. There are 20 homozygotes in GnomAd4. There are 721 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.2862G>C	p.Thr954Thr	synonymous	Exon 23 of 27	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.2940G>C	p.Thr980Thr	synonymous	Exon 22 of 26	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.2862G>C	p.Thr954Thr	synonymous	Exon 23 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.2862G>C	p.Thr954Thr	synonymous	Exon 23 of 27	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.2940G>C	p.Thr980Thr	synonymous	Exon 23 of 27	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.2862G>C	p.Thr954Thr	synonymous	Exon 23 of 27	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1538 AN: 152186 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00244 AC: 379 AN: 155462 AF XY: 0.00164

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.00198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000831

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.00102 AC: 1428 AN: 1397676 Hom.: 22 Cov.: 31 AF XY: 0.000856 AC XY: 590 AN XY: 689560

African (AFR) AF: 0.0370 AC: 1168 AN: 31584

American (AMR) AF: 0.00235 AC: 84 AN: 35776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35808

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48284

Middle Eastern (MID) AF: 0.00112 AC: 5 AN: 4468

European-Non Finnish (NFE) AF: 0.0000139 AC: 15 AN: 1079438

Other (OTH) AF: 0.00263 AC: 152 AN: 57902

GnomAD4 genome AF: 0.0101 AC: 1544 AN: 152304 Hom.: 20 Cov.: 32 AF XY: 0.00968 AC XY: 721 AN XY: 74478

African (AFR) AF: 0.0347 AC: 1442 AN: 41556

American (AMR) AF: 0.00523 AC: 80 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.0123

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Colorectal cancer, susceptibility to, 10 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Carcinoma of colon (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
PhyloP100		-2.0
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3219440; hg19: chr19-50919694; COSMIC: COSV99068280; COSMIC: COSV99068280;