19-10545023-C-G

Variant names:

• chr19-10545023-C-G
• rs752968419
• NM_032885.6:c.386C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032885.6(ATG4D):​c.386C>G​(p.Pro129Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P129L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATG4D NM_032885.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.84
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

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.386C>G	p.Pro129Arg	missense	Exon 3 of 10	NP_116274.3
	ATG4D	NM_001281504.2		c.197C>G	p.Pro66Arg	missense	Exon 3 of 10	NP_001268433.1
	ATG4D	NR_104024.2		n.573C>G		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4D	ENST00000309469.9	TSL:1 MANE Select	c.386C>G	p.Pro129Arg	missense	Exon 3 of 10	ENSP00000311318.3	Q86TL0-1
	ATG4D	ENST00000588667.5	TSL:1	n.386C>G		non_coding_transcript_exon	Exon 3 of 9	ENSP00000467407.1	K7EPJ0
	ATG4D	ENST00000588857.5	TSL:1	n.386C>G		non_coding_transcript_exon	Exon 3 of 10	ENSP00000468290.1	K7ERK1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459222 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725852

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110820

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.28
Sift	Benign	0.044	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.71
MutPred		0.65		Gain of MoRF binding (P = 0.0105)
MVP		0.68
MPC		1.0
ClinPred		1.0	D
GERP RS		3.8
PromoterAI		0.15	Neutral
Varity_R		0.66
gMVP		0.54
Mutation Taster		=44/56	disease causing

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: rs752968419; hg19: chr19-10655699;