chr15-42726386-T-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_138477.4(CDAN1):c.3128A>T(p.Asp1043Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000469 in 1,598,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
CDAN1
NM_138477.4 missense
NM_138477.4 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 5.01
Genes affected
CDAN1 (HGNC:1713): (codanin 1) This gene encodes a protein that appears to play a role in nuclear envelope integrity, possibly related to microtubule attachments. Mutations in this gene cause congenital dyserythropoietic anemia type I, a disease resulting in morphological and functional abnormalities of erythropoiesis. [provided by RefSeq, Jul 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.934
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDAN1 | NM_138477.4 | c.3128A>T | p.Asp1043Val | missense_variant | 24/28 | ENST00000356231.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDAN1 | ENST00000356231.4 | c.3128A>T | p.Asp1043Val | missense_variant | 24/28 | 1 | NM_138477.4 | P1 | |
CDAN1 | ENST00000562465.5 | c.*30A>T | 3_prime_UTR_variant, NMD_transcript_variant | 11/15 | 1 | ||||
CDAN1 | ENST00000643434.1 | c.*2259A>T | 3_prime_UTR_variant, NMD_transcript_variant | 22/25 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000135 AC: 3AN: 222378Hom.: 0 AF XY: 0.00000830 AC XY: 1AN XY: 120446
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GnomAD4 exome AF: 0.0000491 AC: 71AN: 1446820Hom.: 0 Cov.: 33 AF XY: 0.0000459 AC XY: 33AN XY: 718352
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74310
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 29, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 13, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 21750). This missense change has been observed in individual(s) with congenital dyserythropoietic anemia (PMID: 12434312, 32518175). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs80338698, gnomAD 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1043 of the CDAN1 protein (p.Asp1043Val). - |
Congenital dyserythropoietic anemia, type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 10, 2018 | The CDAN1 c.3128A>T (p.Asp1043Val) missense variant is reported to be one of the most common pathogenic congenital dyserythropoietic anemia (CDA) variants in the European population, accounting for approximately 5% (4/75) of the disease-causing alleles (Tamary and Dgany 2009). Only one study was identified in the literature, in which the p.Asp1043Val variant was identified in a compound heterozygous state with a stop-gained variant in one patient with CDA (Dgany et al. 2002). The p.Asp1043Val variant was absent from 180 controls and is reported at a frequency of 0.00003019 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence, the p.Asp1043Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital dyserythropoietic anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at