rs769655007

Variant names:

• chr12-122208412-G-A
• rs769655007
• NM_001371333.1:c.689C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001371333.1(DIABLO):​c.689C>T​(p.Ser230Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S230S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: DIABLO NM_001371333.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.178
• Publications: 0 publications found

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]

ENSG00000256861 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.062180966).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371333.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIABLO	NM_001371333.1	MANE Select	c.689C>T	p.Ser230Leu	missense	Exon 6 of 6	NP_001358262.1	A0A0S2Z5U7
	B3GNT4	NM_030765.4	MANE Select	c.*1024G>A		3_prime_UTR	Exon 3 of 3	NP_110392.1	Q9C0J1-1
	DIABLO	NM_019887.6		c.689C>T	p.Ser230Leu	missense	Exon 7 of 7	NP_063940.1	A0A0S2Z5U7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIABLO	ENST00000464942.7	TSL:1 MANE Select	c.689C>T	p.Ser230Leu	missense	Exon 6 of 6	ENSP00000442360.2	Q9NR28-1
	DIABLO	ENST00000353548.11	TSL:1	c.557C>T	p.Ser186Leu	missense	Exon 5 of 5	ENSP00000320343.6	Q9NR28-3
	B3GNT4	ENST00000324189.5	TSL:1 MANE Select	c.*1024G>A		3_prime_UTR	Exon 3 of 3	ENSP00000319636.4	Q9C0J1-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249458 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460874 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726670

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.000188 AC: 1 AN: 5306

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60318

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.1
DANN	Benign	0.72
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.18
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Benign	0.28	T
Sift4G	Benign	0.27	T
Polyphen		0.0030	B
Vest4		0.067
MutPred		0.43		Loss of phosphorylation at S230 (P = 7e-04)
MVP		0.46
MPC		0.024
ClinPred		0.018	T
GERP RS		1.8
Varity_R		0.054
gMVP		0.054
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs769655007; hg19: chr12-122692959;