dbSNP rs1347805493: ATG4D:p.Pro56Gln (chr19-10544257-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032885.6(ATG4D):c.167C>A(p.Pro56Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000897 in 1,114,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P56L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

ATG4D
NM_032885.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.44

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04764554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4D	NM_032885.6 link	c.167C>A	p.Pro56Gln	missense_variant	Exon 1 of 10	ENST00000309469.9	NP_116274.3	Q86TL0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG4D	ENST00000309469.9 link	c.167C>A	p.Pro56Gln	missense_variant	Exon 1 of 10	1	NM_032885.6	ENSP00000311318.3		Q86TL0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.97e-7

AC:

AN:

1114998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

529138

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23738

American (AMR)

AF:

0.00

AC:

AN:

9742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14612

East Asian (EAS)

AF:

0.00

AC:

AN:

27506

South Asian (SAS)

AF:

0.00

AC:

AN:

23650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4484

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

930380

Other (OTH)

AF:

0.00

AC:

AN:

44664

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.0

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.014

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.35

M_CAP

Benign

0.0094

MetaRNN

Benign

0.048

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

1.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.0

REVEL

Benign

0.057

Sift

Benign

0.63

Sift4G

Benign

0.31

Polyphen

0.0040

Vest4

0.071

MutPred

0.21

Loss of glycosylation at P56 (P = 0.0402);

MVP

0.072

MPC

0.31

ClinPred

0.045

GERP RS

0.76

PromoterAI

-0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.020

gMVP

0.32

Mutation Taster

=98/2

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over