16-89957556-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001242818.2(DEF8):​c.268G>A​(p.Glu90Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000694 in 1,440,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

DEF8
NM_001242818.2 missense

Scores

4
5
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.21
Variant links:
Genes affected
DEF8 (HGNC:25969): (differentially expressed in FDCP 8 homolog) Predicted to enable metal ion binding activity. Predicted to be involved in lysosome localization; positive regulation of bone resorption; and positive regulation of ruffle assembly. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38679767).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DEF8NM_001242818.2 linkuse as main transcriptc.268G>A p.Glu90Lys missense_variant 5/13 ENST00000563594.6 NP_001229747.1 Q6ZN54-5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DEF8ENST00000563594.6 linkuse as main transcriptc.268G>A p.Glu90Lys missense_variant 5/131 NM_001242818.2 ENSP00000458019.1 Q6ZN54-5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000935
AC:
2
AN:
213854
Hom.:
0
AF XY:
0.00000865
AC XY:
1
AN XY:
115666
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000326
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:
0.0000106
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000694
AC:
10
AN:
1440590
Hom.:
0
Cov.:
31
AF XY:
0.00000979
AC XY:
7
AN XY:
714816
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000241
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:
0.00000726
Gnomad4 OTH exome
AF:
0.0000168
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 12, 2024The c.451G>A (p.E151K) alteration is located in exon 5 (coding exon 4) of the DEF8 gene. This alteration results from a G to A substitution at nucleotide position 451, causing the glutamic acid (E) at amino acid position 151 to be replaced by a lysine (K). 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
0.12
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.11
.;T;.;.;T;.;T;.;T;.;.;T;T;.;.;.;.;.
Eigen
Uncertain
0.34
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
.;D;D;D;D;D;D;D;D;D;.;D;D;.;D;D;D;D
M_CAP
Benign
0.065
D
MetaRNN
Benign
0.39
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.3
.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-2.1
N;D;.;.;D;D;N;D;N;N;N;D;D;N;N;N;N;N
REVEL
Benign
0.14
Sift
Uncertain
0.025
D;D;.;.;D;D;D;D;T;D;D;D;D;D;T;D;D;T
Sift4G
Uncertain
0.019
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.64
P;.;P;P;.;.;.;.;P;.;P;.;.;P;.;.;P;.
Vest4
0.58
MutPred
0.33
.;.;.;.;.;.;.;.;Gain of ubiquitination at E151 (P = 0.0325);.;.;.;.;.;.;.;.;.;
MVP
0.71
MPC
0.14
ClinPred
0.70
D
GERP RS
4.1
Varity_R
0.13
gMVP
0.45

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.

Other links and lift over

dbSNP: rs778842562; hg19: chr16-90023964; API