rs80338698

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.01

Variant links:

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]

CDAN1 links:

Genome browser will be placed here

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 linkuse as main transcript	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 linkuse as main transcript	c.3128A>T	p.Asp1043Val	missense_variant	24/28	1	NM_138477.4	P1	Q8IWY9-2
CDAN1	ENST00000562465.5 linkuse as main transcript	c.*30A>T		3_prime_UTR_variant, NMD_transcript_variant	11/15	1
CDAN1	ENST00000643434.1 linkuse as main transcript	c.*2259A>T		3_prime_UTR_variant, NMD_transcript_variant	22/25

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000135

AC:

AN:

222378

Hom.:

AF XY:

0.00000830

AC XY:

AN XY:

120446

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000302

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000491

AC:

AN:

1446820

Hom.:

Cov.:

AF XY:

0.0000459

AC XY:

AN XY:

718352

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000624

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000453

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	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 29, 2021	- -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.34

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.55

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.84

Sift

Benign

0.031

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.84

MVP

0.95

MPC

0.54

ClinPred

0.84

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.74

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over