19-10544257-C-G

Variant names:

• chr19-10544257-C-G
• rs1347805493
• NM_032885.6:c.167C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032885.6(ATG4D):​c.167C>G​(p.Pro56Arg) 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

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=0.065603286).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032885.6. 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
	ATG4D	NM_032885.6	MANE Select	c.167C>G	p.Pro56Arg	missense	Exon 1 of 10	NP_116274.3
	ATG4D	NM_001281504.2		c.-97C>G		5_prime_UTR	Exon 1 of 10	NP_001268433.1
	ATG4D	NR_104024.2		n.354C>G		non_coding_transcript_exon	Exon 1 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4D	ENST00000309469.9	TSL:1 MANE Select	c.167C>G	p.Pro56Arg	missense	Exon 1 of 10	ENSP00000311318.3	Q86TL0-1
	ATG4D	ENST00000588667.5	TSL:1	n.167C>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000467407.1	K7EPJ0
	ATG4D	ENST00000588857.5	TSL:1	n.167C>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000468290.1	K7ERK1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.97e-7 AC: 1 AN: 1114998 Hom.: 0 Cov.: 31 AF XY: 0.00000189 AC XY: 1 AN XY: 529138

African (AFR) AF: 0.00 AC: 0 AN: 23738

American (AMR) AF: 0.00 AC: 0 AN: 9742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14612

East Asian (EAS) AF: 0.00 AC: 0 AN: 27506

South Asian (SAS) AF: 0.00 AC: 0 AN: 23650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4484

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 930380

Other (OTH) AF: 0.00 AC: 0 AN: 44664

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.0
DANN	Benign	0.50
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.15
Sift	Benign	0.095	T
Sift4G	Benign	0.13	T
Polyphen		0.089	B
Vest4		0.040
MutPred		0.24		Loss of glycosylation at P56 (P = 0.0402)
MVP		0.095
MPC		0.33
ClinPred		0.10	T
GERP RS		0.76
PromoterAI		-0.025	Neutral
Varity_R		0.035
gMVP		0.34
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1347805493; hg19: chr19-10654933;