12-122208422-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001371333.1(DIABLO):c.679C>T(p.Arg227Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,348 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DIABLO
NM_001371333.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.286

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]

DIABLO links:

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]

B3GNT4 links:

ENSG00000256861 (HGNC:):

ENSG00000256861 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1174894).

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIABLO	NM_001371333.1 link	c.679C>T	p.Arg227Trp	missense_variant	Exon 6 of 6	ENST00000464942.7	NP_001358262.1
B3GNT4	NM_030765.4 link	c.*1034G>A		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	UniProt
DIABLO	ENST00000464942.7 link	c.679C>T	p.Arg227Trp	missense_variant	Exon 6 of 6	1	NM_001371333.1	ENSP00000442360.2	Q9NR28-1
B3GNT4	ENST00000324189.5 link	c.*1034G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_030765.4	ENSP00000319636.4	Q9C0J1-1
ENSG00000256861	ENST00000535844.1 link	n.*473C>T		non_coding_transcript_exon_variant	Exon 16 of 16	2		ENSP00000454454.1	H3BMM5
ENSG00000256861	ENST00000535844.1 link	n.*473C>T		3_prime_UTR_variant	Exon 16 of 16	2		ENSP00000454454.1	H3BMM5

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000441

AC:

AN:

249668

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135034

show subpopulations

Gnomad AFR exome

AF:

0.000495

Gnomad AMR exome

AF:

0.00

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:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461182

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726828

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000125

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.679C>T (p.R227W) alteration is located in exon 7 (coding exon 6) of the DIABLO gene. This alteration results from a C to T substitution at nucleotide position 679, causing the arginine (R) at amino acid position 227 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.48

T;T;T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.83

T;T;.;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.12

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.8

L;.;L;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

N;.;.;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.017

D;.;.;D

Sift4G

Uncertain

0.017

D;D;.;D

Polyphen

0.99

D;.;D;.

Vest4

0.28

MVP

0.83

MPC

0.091

ClinPred

0.075

GERP RS

-3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.10

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over