Genetic Variant NM_052936.5:c.722T>C (chrX-108137978-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_052936.5(ATG4A):c.722T>C(p.Val241Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,199,653 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 279 hemizygotes in GnomAD. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V241G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., 15 hem., cov: 23)

Exomes 𝑓: 0.00076 ( 0 hom. 264 hem. )

Consequence

ATG4A
NM_052936.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.91

Publications

4 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0262793).

BS2

High Hemizygotes in GnomAd4 at 15 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.722T>C	p.Val241Ala	missense	Exon 8 of 13	NP_443168.2
ATG4A	NM_001321287.2		c.491T>C	p.Val164Ala	missense	Exon 9 of 14	NP_001308216.1	Q8WYN0-3
ATG4A	NM_001321288.2		c.491T>C	p.Val164Ala	missense	Exon 8 of 13	NP_001308217.1	Q8WYN0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATG4A	ENST00000372232.8	TSL:1 MANE Select	c.722T>C	p.Val241Ala	missense	Exon 8 of 13	ENSP00000361306.3	Q8WYN0-1
ATG4A	ENST00000345734.7	TSL:1	c.628+94T>C		intron	N/A	ENSP00000298131.5	Q8WYN0-2
ATG4A	ENST00000372246.7	TSL:1	n.*880T>C		non_coding_transcript_exon	Exon 9 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

111266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000669

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000282

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00116

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000622

Gnomad OTH

AF:

0.00133

GnomAD2 exomes

AF:

0.000781

AC:

133

AN:

170298

AF XY:

0.000990

show subpopulations

Gnomad AFR exome

AF:

0.0000765

Gnomad AMR exome

AF:

0.000728

Gnomad ASJ exome

AF:

0.000159

Gnomad EAS exome

AF:

0.0000735

Gnomad FIN exome

AF:

0.00105

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.00144

GnomAD4 exome

AF:

0.000757

AC:

824

AN:

1088333

Hom.:

Cov.:

AF XY:

0.000743

AC XY:

264

AN XY:

355229

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26265

American (AMR)

AF:

0.000784

AC:

AN:

34438

Ashkenazi Jewish (ASJ)

AF:

0.000107

AC:

AN:

18710

East Asian (EAS)

AF:

0.00

AC:

AN:

30113

South Asian (SAS)

AF:

0.0000193

AC:

AN:

51733

European-Finnish (FIN)

AF:

0.000797

AC:

AN:

40141

Middle Eastern (MID)

AF:

0.000245

AC:

AN:

4076

European-Non Finnish (NFE)

AF:

0.000878

AC:

735

AN:

837157

Other (OTH)

AF:

0.000569

AC:

AN:

45700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000467

AC:

AN:

111320

Hom.:

Cov.:

AF XY:

0.000447

AC XY:

AN XY:

33524

show subpopulations

African (AFR)

AF:

0.0000654

AC:

AN:

30589

American (AMR)

AF:

0.000668

AC:

AN:

10480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.000283

AC:

AN:

3537

South Asian (SAS)

AF:

0.00

AC:

AN:

2598

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

6013

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000622

AC:

AN:

53041

Other (OTH)

AF:

0.00132

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.00126

Hom.:

Bravo

AF:

0.000438

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.000898

AC:

109

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

0.18

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.087

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

M_CAP

Benign

0.062

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

2.9

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.8

REVEL

Benign

0.087

Sift

Benign

0.17

Sift4G

Benign

0.22

Polyphen

0.0010

Vest4

0.098

MVP

0.45

MPC

0.48

ClinPred

0.015

GERP RS

5.4

Varity_R

0.17

gMVP

0.46

Mutation Taster

=74/26

polymorphism (auto)

(source)

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

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