rs199898020

chr12-122224516-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001371333.1(DIABLO):c.179C>T(p.Ala60Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000355 in 1,613,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: DIABLO NM_001371333.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.36

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18883106).
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIABLO	NM_001371333.1	c.179C>T	p.Ala60Val	missense_variant	2/6	ENST00000464942.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIABLO	ENST00000464942.7	c.179C>T	p.Ala60Val	missense_variant	2/6	1	NM_001371333.1	P1

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 151680 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

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: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251436 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135890

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000373 AC: 545 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.000351 AC XY: 255 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000460

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000178 AC: 27 AN: 151680 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 74004

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.0000660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000334 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000491

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 23, 2023	The c.179C>T (p.A60V) alteration is located in exon 3 (coding exon 2) of the DIABLO gene. This alteration results from a C to T substitution at nucleotide position 179, causing the alanine (A) at amino acid position 60 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2016	The p.Ala60Val variant in DIABLO has not been previously reported in individuals with hearing loss and has been identified in 14/66736 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1 99898020). Although this variant has been seen in the general population, its f requency is not high enough to rule out a pathogenic role. The alanine (Ala) at position 60 is not well conserved across species, with 1 mammal and several bird s and reptiles having a valine (Val) at this position, suggesting that a change to a valine residue at this position may be tolerated. Additional computational prediction tools do not provide strong support for or against an impact the prot ein. In summary, while the clinical significance of the p.Ala60Val variant is u ncertain. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 04, 2023	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 228570). This variant has not been reported in the literature in individuals affected with DIABLO-related conditions. This variant is present in population databases (rs199898020, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 60 of the DIABLO protein (p.Ala60Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.75	T;.;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.86	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.85	N;.;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.36	T;.;T;.
Sift4G	Benign	0.26	T;.;T;.
Polyphen		0.0010	B;B;.;.
Vest4		0.18
MVP		0.70
MPC		0.025
ClinPred		0.074	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.38
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199898020; hg19: chr12-122709063;