Genetic Variant NM_013325.5:c.583T>G (chr2-241666689-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013325.5(ATG4B):c.583T>G(p.Phe195Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

ATG4B
NM_013325.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.539

Publications

1 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047582984).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4B	NM_013325.5	MANE Select	c.583T>G	p.Phe195Val	missense	Exon 8 of 13	NP_037457.3
	ATG4B	NM_178326.3		c.583T>G	p.Phe195Val	missense	Exon 8 of 13	NP_847896.1	Q9Y4P1-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATG4B	ENST00000404914.8	TSL:1 MANE Select	c.583T>G	p.Phe195Val	missense	Exon 8 of 13	ENSP00000384259.3	Q9Y4P1-1
ATG4B	ENST00000482507.5	TSL:1	n.663T>G		non_coding_transcript_exon	Exon 9 of 13
ATG4B	ENST00000902606.1		c.766T>G	p.Phe256Val	missense	Exon 9 of 14	ENSP00000572665.1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000274

AC:

AN:

248158

AF XY:

0.000267

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000552

Gnomad ASJ exome

AF:

0.00289

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.000138

AC:

202

AN:

1461170

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

726806

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.000515

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00272

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86100

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000774

AC:

AN:

1111730

Other (OTH)

AF:

0.000315

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000217

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41562

American (AMR)

AF:

0.000981

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000424

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000356

AC:

ExAC

AF:

0.000190

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

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

0.080

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.5

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.061

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.71

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0048

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.75

PhyloP100

0.54

PrimateAI

Benign

0.35

PROVEAN

Benign

0.56

REVEL

Benign

0.066

Sift

Benign

0.53

Sift4G

Benign

0.51

Polyphen

0.0

Vest4

0.070

MVP

0.23

MPC

0.59

ClinPred

0.0039

GERP RS

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.19

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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