15-36657840-A-G

Variant names:

• chr15-36657840-A-G
• rs587777101
• ENST00000562877.5:c.-14A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_032499.6(CDIN1):​c.-14A>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000685 in 1,459,208 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 pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDIN1 NM_032499.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 5.01
• Publications: 6 publications found

Genes affected

CDIN1 (HGNC:26929): (CDAN1 interacting nuclease 1) This gene encodes a protein with two predicted helix-turn-helix domains. Mutations in this gene were found in families with congenital dyserythropoietic anemia type Ib. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

CDIN1 Gene-Disease associations (from GenCC):

• congenital dyserythropoietic anemia type type 1B

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000261191 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-36657840-A-G is Pathogenic according to our data. Variant chr15-36657840-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 97058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2802382). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032499.6. 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
	CDIN1	NM_001321759.2	MANE Select	c.281A>G	p.Tyr94Cys	missense	Exon 5 of 11	NP_001308688.1	Q9Y2V0-1
	CDIN1	NM_001290232.2		c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 11	NP_001277161.1	Q9Y2V0-2
	CDIN1	NM_001321756.2		c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	NP_001308685.1	Q9Y2V0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDIN1	ENST00000562877.5	TSL:1	c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 5 of 11	ENSP00000457854.1	Q9Y2V0-2
	CDIN1	ENST00000567389.5	TSL:1	c.-14A>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 12	ENSP00000456736.1	Q9Y2V0-2
	CDIN1	ENST00000566621.6	TSL:5 MANE Select	c.281A>G	p.Tyr94Cys	missense	Exon 5 of 11	ENSP00000455397.1	Q9Y2V0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459208 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725650

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110656

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital dyserythropoietic anemia type type 1B (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.0
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Benign	0.050	D
Sift4G	Uncertain	0.035	D
Polyphen		0.90	P
Vest4		0.62
MutPred		0.36		Loss of phosphorylation at Y94 (P = 0.0403)
MVP		0.28
MPC		0.43
ClinPred		0.66	D
GERP RS		4.1
Varity_R		0.10
gMVP		0.67
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs587777101; hg19: chr15-36950041;