rs387906893

Positions:

• chr12-122216808-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. 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).

• 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

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]

ENSG00000256861 (HGNC:):

ACMG classification

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, 0.812
• 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 id is 30449.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr12-122216808-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIABLO	NM_001371333.1	c.377C>T	p.Ser126Leu	missense_variant	4/6	ENST00000464942.7	NP_001358262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIABLO	ENST00000464942.7	c.377C>T	p.Ser126Leu	missense_variant	4/6	1	NM_001371333.1	ENSP00000442360.2
ENSG00000256861	ENST00000535844.1	n.*171C>T		non_coding_transcript_exon_variant	14/16	2		ENSP00000454454.1
ENSG00000256861	ENST00000535844.1	n.*171C>T		3_prime_UTR_variant	14/16	2		ENSP00000454454.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 126 of the DIABLO protein (p.Ser126Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with deafness (PMID: 21722859). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30449). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DIABLO function (PMID: 21722859). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	Published functional studies demonstrate a damaging effect of protein degradation (Cheng et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21722859) -

Autosomal dominant nonsyndromic hearing loss 64 Pathogenic:1

Pathogenic, flagged submission

literature only

OMIM

Jul 15, 2011

- -

Computational scores

Source: dbNSFP v4.3

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;T;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;.;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.8	M;.;M;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.7	D;.;.;D;.;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.028	D;.;.;D;.;.
Sift4G	Benign	0.070	T;T;.;T;.;.
Polyphen		1.0	D;.;D;.;.;.
Vest4		0.84
MutPred		0.58		Loss of disorder (P = 0.025);.;Loss of disorder (P = 0.025);.;Loss of disorder (P = 0.025);.;
MVP		0.91
MPC		0.20
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.46
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906893; hg19: chr12-122701355;