GeneBe

rs1430893033

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001371333.1(DIABLO):​c.634_635delCA​(p.Gln212AspfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000186 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DIABLO
NM_001371333.1 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.28
Variant links:
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]
B3GNT4 (HGNC:15683): (UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 4) This gene encodes a member of the beta-1,3-N-acetylglucosaminyltransferase protein family. The encoded enzyme is involved in the biosynthesis of poly-N-acetyllactosamine chains and prefers lacto-N-neotetraose as a substrate. It is a type II transmembrane protein. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DIABLONM_001371333.1 linkc.634_635delCA p.Gln212AspfsTer17 frameshift_variant Exon 6 of 6 ENST00000464942.7 NP_001358262.1
B3GNT4NM_030765.4 linkc.*1080_*1081delTG 3_prime_UTR_variant Exon 3 of 3 ENST00000324189.5 NP_110392.1 Q9C0J1-1A0A024RBT1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DIABLOENST00000464942.7 linkc.634_635delCA p.Gln212AspfsTer17 frameshift_variant Exon 6 of 6 1 NM_001371333.1 ENSP00000442360.2 Q9NR28-1
B3GNT4ENST00000324189.5 linkc.*1080_*1081delTG 3_prime_UTR_variant Exon 3 of 3 1 NM_030765.4 ENSP00000319636.4 Q9C0J1-1
ENSG00000256861ENST00000535844.1 linkn.*428_*429delCA non_coding_transcript_exon_variant Exon 16 of 16 2 ENSP00000454454.1 H3BMM5
ENSG00000256861ENST00000535844.1 linkn.*428_*429delCA 3_prime_UTR_variant Exon 16 of 16 2 ENSP00000454454.1 H3BMM5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152240
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461838
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152240
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 21, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Gln212AspfsX17 variant in DIABLO has not been previously reported in individuals with hearing loss, but has been identified in 0.06% (1/1558) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 212 and leads to a premature termination codon 17 amino acids downstream. However, this termination codon occurs within the last exon and is therefore likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Furthermore, loss of function is not a known disease mechanism for DIABLO-related hearing loss. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1430893033; hg19: chr12-122693012; API