15-42725228-T-G

Variant names:

• chr15-42725228-T-G
• rs16957091
• NM_138477.4:c.3474A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138477.4(CDAN1):​c.3474A>C​(p.Leu1158Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,613,572 control chromosomes in the GnomAD database, including 75,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (18329 hom., cov: 32)
  • Exomes 𝑓: 0.26 (57421 hom.)
• Consequence: CDAN1 NM_138477.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.474
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• anemia, congenital dyserythropoietic, type 1a

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital dyserythropoietic anemia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital dyserythropoietic anemia

  Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 15-42725228-T-G is Benign according to our data. Variant chr15-42725228-T-G is described in ClinVar as Benign. ClinVar VariationId is 262376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.474 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138477.4. 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
	CDAN1	NM_138477.4	MANE Select	c.3474A>C	p.Leu1158Leu	synonymous	Exon 27 of 28	NP_612486.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDAN1	ENST00000356231.4	TSL:1 MANE Select	c.3474A>C	p.Leu1158Leu	synonymous	Exon 27 of 28	ENSP00000348564.3
	CDAN1	ENST00000562465.5	TSL:1	n.*376A>C		non_coding_transcript_exon	Exon 14 of 15	ENSP00000454246.1
	CDAN1	ENST00000562465.5	TSL:1	n.*376A>C		3_prime_UTR	Exon 14 of 15	ENSP00000454246.1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61627 AN: 151974 Hom.: 18268 Cov.: 32

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.356

GnomAD2 exomes AF: 0.289 AC: 72666 AN: 251402 AF XY: 0.290

Gnomad AFR exome AF: 0.850

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.256 AC: 374211 AN: 1461480 Hom.: 57421 Cov.: 33 AF XY: 0.261 AC XY: 189605 AN XY: 727086

African (AFR) AF: 0.867 AC: 29020 AN: 33480

American (AMR) AF: 0.156 AC: 6989 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8370 AN: 26136

East Asian (EAS) AF: 0.248 AC: 9859 AN: 39698

South Asian (SAS) AF: 0.439 AC: 37825 AN: 86248

European-Finnish (FIN) AF: 0.253 AC: 13526 AN: 53414

Middle Eastern (MID) AF: 0.309 AC: 1785 AN: 5768

European-Non Finnish (NFE) AF: 0.224 AC: 249268 AN: 1111636

Other (OTH) AF: 0.291 AC: 17569 AN: 60380

GnomAD4 genome AF: 0.406 AC: 61743 AN: 152092 Hom.: 18329 Cov.: 32 AF XY: 0.402 AC XY: 29905 AN XY: 74348

African (AFR) AF: 0.840 AC: 34874 AN: 41500

American (AMR) AF: 0.220 AC: 3368 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3464

East Asian (EAS) AF: 0.251 AC: 1297 AN: 5160

South Asian (SAS) AF: 0.427 AC: 2057 AN: 4822

European-Finnish (FIN) AF: 0.255 AC: 2696 AN: 10576

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15426 AN: 67960

Other (OTH) AF: 0.352 AC: 741 AN: 2108

Alfa AF: 0.265 Hom.: 10585

Bravo AF: 0.418

Asia WGS AF: 0.359 AC: 1249 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Anemia, congenital dyserythropoietic, type 1a (1)
-	-	1	Congenital dyserythropoietic anemia, type I (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.0
DANN	Benign	0.72
PhyloP100		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs16957091; hg19: chr15-43017426; COSMIC: COSV51900020; COSMIC: COSV51900020;