dbSNP rs146980867: ATG4A:p.Val171Ile (chrX-108137134-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_052936.5(ATG4A):c.511G>A(p.Val171Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000523 in 1,207,155 control chromosomes in the GnomAD database, including 1 homozygotes. There are 199 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., 17 hem., cov: 23)

Exomes 𝑓: 0.00052 ( 1 hom. 182 hem. )

Consequence

ATG4A
NM_052936.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.02

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10917336).

BS2

High Hemizygotes in GnomAd4 at 17 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.511G>A	p.Val171Ile	missense	Exon 7 of 13	NP_443168.2
ATG4A	NM_178270.4		c.511G>A	p.Val171Ile	missense	Exon 7 of 12	NP_840054.1	Q8WYN0-2
ATG4A	NM_001321287.2		c.280G>A	p.Val94Ile	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.511G>A	p.Val171Ile	missense	Exon 7 of 13	ENSP00000361306.3	Q8WYN0-1
ATG4A	ENST00000345734.7	TSL:1	c.511G>A	p.Val171Ile	missense	Exon 7 of 12	ENSP00000298131.5	Q8WYN0-2
ATG4A	ENST00000372246.7	TSL:1	n.*669G>A		non_coding_transcript_exon	Exon 8 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes

AF:

0.000540

AC:

AN:

112935

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000558

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:

0.000899

Gnomad OTH

AF:

0.00131

GnomAD2 exomes

AF:

0.000343

AC:

AN:

180941

AF XY:

0.000244

show subpopulations

Gnomad AFR exome

AF:

0.000307

Gnomad AMR exome

AF:

0.000372

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000568

Gnomad OTH exome

AF:

0.000450

GnomAD4 exome

AF:

0.000521

AC:

570

AN:

1094167

Hom.:

Cov.:

AF XY:

0.000506

AC XY:

182

AN XY:

359817

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26275

American (AMR)

AF:

0.000315

AC:

AN:

34975

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19240

East Asian (EAS)

AF:

0.00

AC:

AN:

29931

South Asian (SAS)

AF:

0.00

AC:

AN:

53737

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40274

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.000647

AC:

543

AN:

839700

Other (OTH)

AF:

0.000261

AC:

AN:

45918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000540

AC:

AN:

112988

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

35138

show subpopulations

African (AFR)

AF:

0.000161

AC:

AN:

31137

American (AMR)

AF:

0.000558

AC:

AN:

10759

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3606

South Asian (SAS)

AF:

0.00

AC:

AN:

2726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6248

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000899

AC:

AN:

53408

Other (OTH)

AF:

0.00129

AC:

AN:

1548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000525

Hom.:

Bravo

AF:

0.000442

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000264

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.092

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.7

PhyloP100

9.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.62

REVEL

Benign

0.17

Sift

Benign

0.37

Sift4G

Benign

0.19

Polyphen

0.71

Vest4

0.67

MVP

0.73

MPC

1.1

ClinPred

0.054

GERP RS

5.2

Varity_R

0.25

gMVP

0.42

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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