chr19-10544813-G-A

Position:

chr19-10544813-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032885.6(ATG4D):c.266G>A(p.Ser89Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00099 in 1,614,156 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

ATG4D
NM_032885.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 3.24

Variant links:

Genes affected

ATG4D (HGNC:20789): (autophagy related 4D 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 belongs to the autophagy-related protein 4 (Atg4) family of C54 endopeptidases. Members of this family encode proteins that play a role in the biogenesis of autophagosomes, which sequester the cytosol and organelles for degradation by lysosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ATG4D links:

ATG4D (HGNC:):

ATG4D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03791347).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG4D	NM_032885.6 linkuse as main transcript	c.266G>A	p.Ser89Asn	missense_variant	2/10	ENST00000309469.9	NP_116274.3	Q86TL0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG4D	ENST00000309469.9 linkuse as main transcript	c.266G>A	p.Ser89Asn	missense_variant	2/10	1	NM_032885.6	ENSP00000311318.3		Q86TL0-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000569

AC:

143

AN:

251250

Hom.:

AF XY:

0.000552

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000971

Gnomad NFE exome

AF:

0.000915

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.00102

AC:

1486

AN:

1461804

Hom.:

Cov.:

AF XY:

0.000971

AC XY:

706

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000899

Gnomad4 NFE exome

AF:

0.00123

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000735

AC:

112

AN:

152352

Hom.:

Cov.:

AF XY:

0.000711

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00135

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000759

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.00185

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ASHER

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health

Oct 17, 2021

Variant likely pathogenic in combination wiith a pathogenic variant. Part of a compound heterozygous pair. ATG4D-related disorder; ASHER (ATG4D-related, Spectrum of cerebellar findings, Hypotonia and joint laxity, Early onset, Regression or delay) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.266G>A (p.S89N) alteration is located in exon 2 (coding exon 2) of the ATG4D gene. This alteration results from a G to A substitution at nucleotide position 266, causing the serine (S) at amino acid position 89 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neurodevelopmental disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Sep 21, 2024

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder, MONDO:0700092, ATG4D-related. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (164 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated cryptic mitochondrial signal peptide (PMID: 36765070). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been classified a VUS in ClinVar. This variant has also been observed in a compound heterozygous individual with a neurodevelopmental disorder characterised by speech and motor impairment (PMID: 36765070). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. This variant had in vitro GABAR-APL1 priming activity comparable to wildtype activity in an ATG4 tetra knockout cell line (PMID: 36765070). Furthermore, partial reversion was observed in mATG8s lipidation, however this was not a significant finding (PMID: 33795848). (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

T;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.21

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.12

Sift

Benign

0.12

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.33

B;.

Vest4

0.22

MVP

0.45

MPC

1.0

ClinPred

0.049

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.24

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