chr19-50403034-G-A

Variant names:

• chr19-50403034-G-A
• rs56022846
• NM_002691.4:c.971-19G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002691.4(POLD1):​c.971-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,552,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.906
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-50403034-G-A is Benign according to our data. Variant chr19-50403034-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 246155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.971-19G>A		intron	N/A	NP_002682.2	P28340
	POLD1	NM_001308632.1		c.971-19G>A		intron	N/A	NP_001295561.1	M0R2B7
	POLD1	NM_001256849.1		c.971-19G>A		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.971-19G>A		intron	N/A	ENSP00000406046.1	P28340
	POLD1	ENST00000595904.6	TSL:1	c.971-19G>A		intron	N/A	ENSP00000472445.1	M0R2B7
	POLD1	ENST00000599857.7	TSL:1	c.971-19G>A		intron	N/A	ENSP00000473052.1	P28340

Frequencies

GnomAD3 genomes AF: 0.000913 AC: 139 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000238 AC: 37 AN: 155546 AF XY: 0.000206

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.0000801

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 162 AN: 1400474 Hom.: 0 Cov.: 32 AF XY: 0.0000955 AC XY: 66 AN XY: 691076

African (AFR) AF: 0.00417 AC: 132 AN: 31664

American (AMR) AF: 0.0000834 AC: 3 AN: 35958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35862

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49086

Middle Eastern (MID) AF: 0.000714 AC: 4 AN: 5600

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1079676

Other (OTH) AF: 0.000327 AC: 19 AN: 58052

GnomAD4 genome AF: 0.000913 AC: 139 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000846 AC XY: 63 AN XY: 74472

African (AFR) AF: 0.00317 AC: 132 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.00122

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)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.39
DANN	Benign	0.80
PhyloP100		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

Other links and lift over

dbSNP: rs56022846; hg19: chr19-50906291;