19-50417272-G-A

Variant names:

• chr19-50417272-G-A
• rs755695606
• NM_002691.4:c.3218+3G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002691.4(POLD1):​c.3218+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,431,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: POLD1 NM_002691.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005159
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.292
• 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):

• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-50417272-G-A is Benign according to our data. Variant chr19-50417272-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 469329.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.3218+3G>A		splice_region intron	N/A	NP_002682.2
	POLD1	NM_001308632.1		c.3296+3G>A		splice_region intron	N/A	NP_001295561.1
	POLD1	NM_001256849.1		c.3218+3G>A		splice_region intron	N/A	NP_001243778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.3218+3G>A		splice_region intron	N/A	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.3296+3G>A		splice_region intron	N/A	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.3218+3G>A		splice_region intron	N/A	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000470 AC: 1 AN: 212706 AF XY: 0.00000857

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000279 AC: 4 AN: 1431948 Hom.: 0 Cov.: 32 AF XY: 0.00000422 AC XY: 3 AN XY: 710982

African (AFR) AF: 0.00 AC: 0 AN: 32914

American (AMR) AF: 0.00 AC: 0 AN: 42946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 38866

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 84064

European-Finnish (FIN) AF: 0.0000235 AC: 1 AN: 42610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099824

Other (OTH) AF: 0.0000168 AC: 1 AN: 59378

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Colorectal cancer, susceptibility to, 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.8
DANN	Benign	0.84
PhyloP100		-0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.062
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: rs755695606; hg19: chr19-50920529;