12-122208411-C-T

Position:

• chr12-122208411-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001371333.1(DIABLO):​c.690G>A​(p.Ser230=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,613,036 control chromosomes in the GnomAD database, including 3,788 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1974 hom., cov: 32)
  • Exomes 𝑓: 0.010 (1814 hom.)
• Consequence: DIABLO NM_001371333.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.45

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 12-122208411-C-T is Benign according to our data. Variant chr12-122208411-C-T is described in ClinVar as [Benign]. Clinvar id is 226562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIABLO	NM_001371333.1	c.690G>A	p.Ser230=	synonymous_variant	6/6	ENST00000464942.7	NP_001358262.1
B3GNT4	NM_030765.4	c.*1023C>T		3_prime_UTR_variant	3/3	ENST00000324189.5	NP_110392.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIABLO	ENST00000464942.7	c.690G>A	p.Ser230=	synonymous_variant	6/6	1	NM_001371333.1	ENSP00000442360	P1
B3GNT4	ENST00000324189.5	c.*1023C>T		3_prime_UTR_variant	3/3	1	NM_030765.4	ENSP00000319636	A2

Frequencies

GnomAD3 genomes AF: 0.0891 AC: 13550 AN: 152112 Hom.: 1969 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0583

GnomAD3 exomes AF: 0.0247 AC: 6148 AN: 249380 Hom.: 796 AF XY: 0.0185 AC XY: 2498 AN XY: 134920

Gnomad AFR exome AF: 0.313

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0103 AC: 15000 AN: 1460806 Hom.: 1814 Cov.: 31 AF XY: 0.00901 AC XY: 6550 AN XY: 726642

Gnomad4 AFR exome AF: 0.328

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0287

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000789

Gnomad4 OTH exome AF: 0.0232

GnomAD4 genome AF: 0.0892 AC: 13583 AN: 152230 Hom.: 1974 Cov.: 32 AF XY: 0.0865 AC XY: 6435 AN XY: 74436

Gnomad4 AFR AF: 0.306

Gnomad4 AMR AF: 0.0353

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0404 Hom.: 409

Bravo AF: 0.103

EpiCase AF: 0.00207

EpiControl AF: 0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 28, 2015	p.Ser230Ser in exon 7 of DIABLO: This variant is not expected to have clinical s ignificance because it has been identified in 31.1% (3168/10204) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs35426428). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.5
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Other links and lift over

dbSNP: rs35426428; hg19: chr12-122692958;