Variant chr2-241666704-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000404914.8(ATG4B):c.598G>A(p.Asp200Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,042 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 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

ATG4B
ENST00000404914.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37

Variant links:

Genes affected

ATG4B (HGNC:20790): (autophagy related 4B cysteine peptidase) Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ATG4B links:

ATG4B (HGNC:):

ATG4B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0099748075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG4B	NM_013325.5 linkuse as main transcript	c.598G>A	p.Asp200Asn	missense_variant	8/13	ENST00000404914.8	NP_037457.3	Q9Y4P1-1B3KVU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG4B	ENST00000404914.8 linkuse as main transcript	c.598G>A	p.Asp200Asn	missense_variant	8/13	1	NM_013325.5	ENSP00000384259.3		Q9Y4P1-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000291

AC:

AN:

247164

Hom.:

AF XY:

0.000246

AC XY:

AN XY:

134212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000168

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00145

Gnomad NFE exome

AF:

0.000250

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000166

AC:

242

AN:

1460746

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

726552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00165

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000236

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000347

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Mar 16, 2022

The c.598G>A (p.D200N) alteration is located in exon 8 (coding exon 8) of the ATG4B gene. This alteration results from a G to A substitution at nucleotide position 598, causing the aspartic acid (D) at amino acid position 200 to be replaced by an asparagine (N). 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

0.072

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.3

DANN

Uncertain

0.99

DEOGEN2

Benign

0.085

.;.;T;T;T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.62

T;T;T;T;.;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.10

N;N;N;N;N;N

REVEL

Benign

0.049

Sift

Benign

0.13

T;T;T;T;T;T

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

0.017, 0.034

.;B;B;.;.;.

Vest4

0.13

MVP

0.32

MPC

0.45

ClinPred

0.022

GERP RS

2.0

Varity_R

0.040

gMVP

0.18

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