19-50401932-G-T

Variant names:

• chr19-50401932-G-T
• rs1726802
• NM_002691.4:c.463+8G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002691.4(POLD1):​c.463+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0918 in 1,613,850 control chromosomes in the GnomAD database, including 9,681 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2241 hom., cov: 32)
  • Exomes 𝑓: 0.087 (7440 hom.)
• Consequence: POLD1 NM_002691.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002784
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.41
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-50401932-G-T is Benign according to our data. Variant chr19-50401932-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 371890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 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.463+8G>T		splice_region intron	N/A	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.463+8G>T		splice_region intron	N/A	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.463+8G>T		splice_region intron	N/A	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.463+8G>T		splice_region intron	N/A	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.463+8G>T		splice_region intron	N/A	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.463+8G>T		splice_region intron	N/A	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21193 AN: 152004 Hom.: 2235 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0670

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.110 AC: 27712 AN: 250892 AF XY: 0.112

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.0407

Gnomad NFE exome AF: 0.0701

Gnomad OTH exome AF: 0.0992

GnomAD4 exome AF: 0.0869 AC: 126987 AN: 1461728 Hom.: 7440 Cov.: 35 AF XY: 0.0901 AC XY: 65483 AN XY: 727174

African (AFR) AF: 0.298 AC: 9964 AN: 33470

American (AMR) AF: 0.105 AC: 4715 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2764 AN: 26120

East Asian (EAS) AF: 0.165 AC: 6561 AN: 39698

South Asian (SAS) AF: 0.197 AC: 16991 AN: 86250

European-Finnish (FIN) AF: 0.0414 AC: 2212 AN: 53400

Middle Eastern (MID) AF: 0.145 AC: 838 AN: 5766

European-Non Finnish (NFE) AF: 0.0692 AC: 76934 AN: 1111924

Other (OTH) AF: 0.0995 AC: 6008 AN: 60382

GnomAD4 genome AF: 0.140 AC: 21224 AN: 152122 Hom.: 2241 Cov.: 32 AF XY: 0.138 AC XY: 10290 AN XY: 74380

African (AFR) AF: 0.293 AC: 12168 AN: 41490

American (AMR) AF: 0.103 AC: 1575 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3470

East Asian (EAS) AF: 0.152 AC: 780 AN: 5146

South Asian (SAS) AF: 0.200 AC: 966 AN: 4826

European-Finnish (FIN) AF: 0.0359 AC: 381 AN: 10610

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0670 AC: 4555 AN: 67978

Other (OTH) AF: 0.126 AC: 266 AN: 2110

Alfa AF: 0.0991 Hom.: 489

Bravo AF: 0.151

Asia WGS AF: 0.185 AC: 642 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Colorectal cancer, susceptibility to, 10 (3)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	Mandibular hypoplasia-deafness-progeroid syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.28
DANN	Benign	0.83
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs1726802; hg19: chr19-50905189; COSMIC: COSV70955584; COSMIC: COSV70955584;