Genetic Variant ATG4A:p.Glu180Asp (chrX-108137163-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_052936.5(ATG4A):c.540A>C(p.Glu180Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,201,649 control chromosomes in the GnomAD database, including 50 homozygotes. There are 813 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 24 hom., 348 hem., cov: 23)

Exomes 𝑓: 0.0016 ( 26 hom. 465 hem. )

Consequence

ATG4A
NM_052936.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.10

Publications

2 publications found

Variant links:

Genes affected

ATG4A (HGNC:16489): (autophagy related 4A 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. [provided by RefSeq, Mar 2016]

ATG4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020264179).

BP6

Variant X-108137163-A-C is Benign according to our data. Variant chrX-108137163-A-C is described in ClinVar as Benign. ClinVar VariationId is 791383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1270/112988) while in subpopulation AFR AF = 0.0377 (1174/31112). AF 95% confidence interval is 0.0359. There are 24 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052936.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATG4A	NM_052936.5	MANE Select	c.540A>C	p.Glu180Asp	missense	Exon 7 of 13	NP_443168.2
ATG4A	NM_178270.4		c.540A>C	p.Glu180Asp	missense	Exon 7 of 12	NP_840054.1	Q8WYN0-2
ATG4A	NM_001321287.2		c.309A>C	p.Glu103Asp	missense	Exon 8 of 14	NP_001308216.1	Q8WYN0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATG4A	ENST00000372232.8	TSL:1 MANE Select	c.540A>C	p.Glu180Asp	missense	Exon 7 of 13	ENSP00000361306.3	Q8WYN0-1
ATG4A	ENST00000345734.7	TSL:1	c.540A>C	p.Glu180Asp	missense	Exon 7 of 12	ENSP00000298131.5	Q8WYN0-2
ATG4A	ENST00000372246.7	TSL:1	n.*698A>C		non_coding_transcript_exon	Exon 8 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1266

AN:

112933

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0377

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00512

Gnomad ASJ

AF:

0.000752

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000431

Gnomad OTH

AF:

0.00980

GnomAD2 exomes

AF:

0.00349

AC:

621

AN:

177862

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.0396

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.000817

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000438

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00157

AC:

1712

AN:

1088661

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

465

AN XY:

354567

show subpopulations

African (AFR)

AF:

0.0410

AC:

1071

AN:

26152

American (AMR)

AF:

0.00282

AC:

AN:

34779

Ashkenazi Jewish (ASJ)

AF:

0.000784

AC:

AN:

19129

East Asian (EAS)

AF:

0.00

AC:

AN:

29720

South Asian (SAS)

AF:

0.000281

AC:

AN:

53296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40118

Middle Eastern (MID)

AF:

0.00659

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.000393

AC:

328

AN:

835661

Other (OTH)

AF:

0.00346

AC:

158

AN:

45706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0112

AC:

1270

AN:

112988

Hom.:

Cov.:

AF XY:

0.00990

AC XY:

348

AN XY:

35152

show subpopulations

African (AFR)

AF:

0.0377

AC:

1174

AN:

31112

American (AMR)

AF:

0.00511

AC:

AN:

10760

Ashkenazi Jewish (ASJ)

AF:

0.000752

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3606

South Asian (SAS)

AF:

0.00

AC:

AN:

2728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6260

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000431

AC:

AN:

53409

Other (OTH)

AF:

0.00968

AC:

AN:

1550

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00422

Hom.:

191

Bravo

AF:

0.0136

ESP6500AA

AF:

0.0347

AC:

133

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.00400

AC:

486

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

PhyloP100

3.1

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.96

REVEL

Benign

0.045

Sift

Benign

0.18

Sift4G

Benign

0.50

Polyphen

0.023

Vest4

0.24

MutPred

0.41

Gain of ubiquitination at K184 (P = 0.0985)

MVP

0.64

MPC

1.1

ClinPred

0.039

GERP RS

3.7

Varity_R

0.52

gMVP

0.57

Mutation Taster

=77/23

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over