12-122208555-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001371333.1(DIABLO):c.546C>T(p.Thr182=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000946 in 1,613,534 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (3 hom.)
• Consequence: DIABLO NM_001371333.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.49

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-122208555-G-A is Benign according to our data. Variant chr12-122208555-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 514370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.49 with no splicing effect.
• BS2: High AC in GnomAd at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIABLO	NM_001371333.1	c.546C>T	p.Thr182=	synonymous_variant	6/6	ENST00000464942.7
B3GNT4	NM_030765.4	c.*1167G>A		3_prime_UTR_variant	3/3	ENST00000324189.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIABLO	ENST00000464942.7	c.546C>T	p.Thr182=	synonymous_variant	6/6	1	NM_001371333.1	P1
B3GNT4	ENST00000324189.5	c.*1167G>A		3_prime_UTR_variant	3/3	1	NM_030765.4	A2

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000973 AC: 244 AN: 250866 Hom.: 0 AF XY: 0.00102 AC XY: 139 AN XY: 135686

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000967 AC: 1413 AN: 1461204 Hom.: 3 Cov.: 31 AF XY: 0.000988 AC XY: 718 AN XY: 726966

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00578

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000748 AC: 114 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74498

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000767

EpiCase AF: 0.00147

EpiControl AF: 0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Thr182Thr in exon 7 of DIABLO: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.14% (93/66252) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs149387774). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.19
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149387774; hg19: chr12-122693102; COSMIC: COSV57336400; COSMIC: COSV57336400;