chr19-10544124-C-T

Variant names:

• chr19-10544124-C-T
• rs1000543180
• NM_032885.6:c.34C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001281504.2(ATG4D):​c.-230C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000636 in 1,243,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: ATG4D NM_001281504.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.223
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27479598).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281504.2. 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.34C>T	p.Arg12Trp	missense	Exon 1 of 10	NP_116274.3
	ATG4D	NM_001281504.2		c.-230C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001268433.1
	ATG4D	NM_001281504.2		c.-230C>T		5_prime_UTR	Exon 1 of 10	NP_001268433.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4D	ENST00000309469.9	TSL:1 MANE Select	c.34C>T	p.Arg12Trp	missense	Exon 1 of 10	ENSP00000311318.3	Q86TL0-1
	ATG4D	ENST00000588667.5	TSL:1	n.34C>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000467407.1	K7EPJ0
	ATG4D	ENST00000588857.5	TSL:1	n.34C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000468290.1	K7ERK1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000706 AC: 77 AN: 1091070 Hom.: 0 Cov.: 31 AF XY: 0.0000796 AC XY: 41 AN XY: 515272

African (AFR) AF: 0.00 AC: 0 AN: 22796

American (AMR) AF: 0.00 AC: 0 AN: 8304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14236

East Asian (EAS) AF: 0.00 AC: 0 AN: 26380

South Asian (SAS) AF: 0.0000513 AC: 1 AN: 19482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2912

European-Non Finnish (NFE) AF: 0.0000817 AC: 75 AN: 918452

Other (OTH) AF: 0.0000230 AC: 1 AN: 43566

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.22
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Benign	0.045	D
Sift4G	Benign	0.084	T
Polyphen		1.0	D
Vest4		0.22
MutPred		0.17		Loss of MoRF binding (P = 0.0881)
MVP		0.68
MPC		0.42
ClinPred		0.93	D
GERP RS		3.8
PromoterAI		-0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.44
Mutation Taster		=87/13	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: rs1000543180; hg19: chr19-10654800;