12-122208431-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001371333.1(DIABLO):c.670G>A(p.Gly224Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,613,946 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: DIABLO NM_001371333.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.462

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038775206).
• BP6: Variant 12-122208431-C-T is Benign according to our data. Variant chr12-122208431-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 288171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 380 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIABLO	NM_001371333.1	c.670G>A	p.Gly224Arg	missense_variant	6/6	ENST00000464942.7
B3GNT4	NM_030765.4	c.*1043C>T		3_prime_UTR_variant	3/3	ENST00000324189.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIABLO	ENST00000464942.7	c.670G>A	p.Gly224Arg	missense_variant	6/6	1	NM_001371333.1	P1
B3GNT4	ENST00000324189.5	c.*1043C>T		3_prime_UTR_variant	3/3	1	NM_030765.4	A2

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152244 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00863

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000608 AC: 152 AN: 250108 Hom.: 0 AF XY: 0.000421 AC XY: 57 AN XY: 135232

Gnomad AFR exome AF: 0.00772

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000622

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000247 AC: 361 AN: 1461584 Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 162 AN XY: 727066

Gnomad4 AFR exome AF: 0.00792

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00249 AC: 380 AN: 152362 Hom.: 2 Cov.: 33 AF XY: 0.00236 AC XY: 176 AN XY: 74514

Gnomad4 AFR AF: 0.00861

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000482 Hom.: 1

Bravo AF: 0.00283

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000741 AC: 90

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Gly224Arg in exon 7 of DIABLO: This variant is not expected to have clinical s ignificance because it has been identified in 0.77% (79/10230) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs150199226). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2019	- -

DIABLO-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	14
Dann	Benign	0.82
DEOGEN2	Benign	0.25	T;T;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.78	T;T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0039	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.20	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.59	N;.;.;N
REVEL	Benign	0.092
Sift	Benign	0.15	T;.;.;T
Sift4G	Benign	0.41	T;T;.;T
Polyphen		0.0050	B;.;B;.
Vest4		0.11
MutPred		0.47		Gain of helix (P = 0.0496);.;Gain of helix (P = 0.0496);.;
MVP		0.71
MPC		0.036
ClinPred		0.0067	T
GERP RS		0.19
Varity_R		0.068
gMVP		0.087

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: rs150199226; hg19: chr12-122692978;