Variant 16-89955217-A-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001242818.2(DEF8):c.173A>T(p.Glu58Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000329 in 151,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Consequence

DEF8
NM_001242818.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.04

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]

DEF8 links:

DEF8 (HGNC:):

DEF8 links:

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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=0.2686898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEF8	NM_001242818.2 linkuse as main transcript	c.173A>T	p.Glu58Val	missense_variant	4/13	ENST00000563594.6	NP_001229747.1	Q6ZN54-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEF8	ENST00000563594.6 linkuse as main transcript	c.173A>T	p.Glu58Val	missense_variant	4/13	1	NM_001242818.2	ENSP00000458019.1		Q6ZN54-5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74156

show subpopulations

Gnomad4 AFR

AF:

0.0000968

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

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 submitter

clinical testing

Ambry Genetics

Oct 07, 2024

The c.356A>T (p.E119V) alteration is located in exon 4 (coding exon 3) of the DEF8 gene. This alteration results from a A to T substitution at nucleotide position 356, causing the glutamic acid (E) at amino acid position 119 to be replaced by a valine (V). 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

0.25

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.033

.;T;.;.;T;.;T;.;T;.;T;T;.;.;.;.;.

Eigen

Benign

-0.078

Eigen_PC

Benign

0.022

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

.;T;T;T;T;T;T;T;T;.;T;T;.;T;T;T;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.75

.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

N;N;.;.;N;D;N;N;N;N;D;N;N;N;N;N;D

REVEL

Benign

0.11

Sift

Benign

0.058

T;T;.;.;T;T;T;T;D;T;T;T;T;T;D;T;D

Sift4G

Benign

0.079

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D

Polyphen

0.0070

B;.;B;B;.;.;.;.;B;B;.;.;B;.;B;.;.

Vest4

0.51

MutPred

0.25

.;.;.;.;.;.;.;.;Loss of disorder (P = 0.123);.;.;.;.;.;.;.;.;

MVP

0.30

MPC

0.060

ClinPred

0.77

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.25

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