12-122208496-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001371333.1(DIABLO):c.605G>A(p.Arg202Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000083 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: DIABLO NM_001371333.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.745

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009032786).
• BP6: Variant 12-122208496-C-T is Benign according to our data. Variant chr12-122208496-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2440779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIABLO	NM_001371333.1	c.605G>A	p.Arg202Gln	missense_variant	6/6	ENST00000464942.7
B3GNT4	NM_030765.4	c.*1108C>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.605G>A	p.Arg202Gln	missense_variant	6/6	1	NM_001371333.1	P1
B3GNT4	ENST00000324189.5	c.*1108C>T		3_prime_UTR_variant	3/3	1	NM_030765.4	A2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000995 AC: 25 AN: 251268 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135818

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000575 AC: 84 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727206

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74466

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000969 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 64 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 23, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T;T;T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.78	T;T;.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0090	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.7	N;.;N;.
MutationTaster	Benign	0.93	N;N;N;N;N;D
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.50	N;.;.;N
REVEL	Benign	0.12
Sift	Benign	0.54	T;.;.;T
Sift4G	Benign	0.48	T;T;.;T
Polyphen		0.0050	B;.;B;.
Vest4		0.045
MVP		0.63
MPC		0.026
ClinPred		0.018	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.012

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: rs138784666; hg19: chr12-122693043;