chr19-50402602-A-G
Variant summary
Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong
The NM_002691.4(POLD1):c.841-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,572,136 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
Consequence
NM_002691.4 intron
Scores
Clinical Significance
Conservation
Publications
- POLD1-related polyposis and colorectal cancer syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- colorectal cancer, susceptibility to, 10Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
- mandibular hypoplasia-deafness-progeroid syndromeInheritance: 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 polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- immunodeficiency 120Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
- non-severe combined immunodeficiency due to polymerase delta deficiencyInheritance: AR Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Benign. The variant received -12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.841-10A>G | intron_variant | Intron 7 of 26 | ENST00000440232.7 | NP_002682.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152248Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000549 AC: 10AN: 182112 AF XY: 0.0000411 show subpopulations
GnomAD4 exome AF: 0.0000486 AC: 69AN: 1419770Hom.: 0 Cov.: 34 AF XY: 0.0000441 AC XY: 31AN XY: 702480 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152366Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74512 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Benign:2
Variant summary: POLD1 c.841-10A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.3e-05 in 175902 control chromosomes. The observed variant frequency is approximately 4.4 fold above the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.841-10A>G in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with two classifying the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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not provided Benign:2
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Colorectal cancer, susceptibility to, 10 Benign:2
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This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -
Carcinoma of colon Benign:1
The POLD1 c.841-10A>G variant was not identified in the literature nor was it identified in the Cosmic or Clinvitae database. The variant was also identified in dbSNP (ID: rs140160345) as “With Likely benign allele”, ClinVar (classified as likely benign by GeneDx and Invitae; as uncertain significance by Quest Diagnostics Nichols Institute San Juan Capistrano), and LOVD 3.0 (1x) databases. The variant was identified in control databases in 11 of 175902 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 4280 chromosomes (freq: 0.0002), Latino in 1 of 25734 chromosomes (freq: 0.00004), European in 9 of 73424 chromosomes (freq: 0.0001), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at