rs387906893

Variant names:

• chr12-122216808-G-A
• rs387906893
• NM_001371333.1:c.377C>T
• DIABLO p.Ser126Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3 PP5

The NM_001371333.1(DIABLO):​c.377C>T​(p.Ser126Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000617861: Published functional studies demonstrate a damaging effect of protein degradation (Cheng et al., 2011)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIABLO NM_001371333.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.89
• Publications: 10 publications found

Genes affected

DIABLO (HGNC:21528): (diablo IAP-binding mitochondrial protein) This gene encodes an inhibitor of apoptosis protein (IAP)-binding protein. The encoded mitochondrial protein enters the cytosol when cells undergo apoptosis, and allows activation of caspases by binding to inhibitor of apoptosis proteins. Overexpression of the encoded protein sensitizes tumor cells to apoptosis. A mutation in this gene is associated with young-adult onset of nonsyndromic deafness-64. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

DIABLO Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nonsyndromic hearing loss 64

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000256861 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000617861: Published functional studies demonstrate a damaging effect of protein degradation (Cheng et al., 2011); PMID:21722859
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 12-122216808-G-A is Pathogenic according to our data. Variant chr12-122216808-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 30449.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371333.1. 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
	DIABLO	NM_001371333.1	MANE Select	c.377C>T	p.Ser126Leu	missense	Exon 4 of 6	NP_001358262.1	A0A0S2Z5U7
	DIABLO	NM_019887.6		c.377C>T	p.Ser126Leu	missense	Exon 5 of 7	NP_063940.1	A0A0S2Z5U7
	DIABLO	NM_001278342.1		c.245C>T	p.Ser82Leu	missense	Exon 3 of 5	NP_001265271.1	Q9NR28-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIABLO	ENST00000464942.7	TSL:1 MANE Select	c.377C>T	p.Ser126Leu	missense	Exon 4 of 6	ENSP00000442360.2	Q9NR28-1
	DIABLO	ENST00000267169.11	TSL:1	c.377C>T	p.Ser126Leu	missense	Exon 4 of 7	ENSP00000267169.7	A0A2U3TZH2
	DIABLO	ENST00000353548.11	TSL:1	c.245C>T	p.Ser82Leu	missense	Exon 3 of 5	ENSP00000320343.6	Q9NR28-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	Autosomal dominant nonsyndromic hearing loss 64 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.028	D
Sift4G	Benign	0.070	T
Varity_R		0.46
gMVP		0.15
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387906893;

hg19: chr12-122701355;