chr19-10544266-C-T

Variant names:

• chr19-10544266-C-T
• rs1157840967
• NM_032885.6:c.176C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001281504.2(ATG4D):​c.-88C>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 0.0000157 in 1,272,582 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: 0.000016 (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: 3.57
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20829251).

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.176C>T	p.Pro59Leu	missense	Exon 1 of 10	NP_116274.3
	ATG4D	NM_001281504.2		c.-88C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001268433.1
	ATG4D	NM_001281504.2		c.-88C>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.176C>T	p.Pro59Leu	missense	Exon 1 of 10	ENSP00000311318.3	Q86TL0-1
	ATG4D	ENST00000588667.5	TSL:1	n.176C>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000467407.1	K7EPJ0
	ATG4D	ENST00000588857.5	TSL:1	n.176C>T		non_coding_transcript_exon	Exon 1 of 10	ENSP00000468290.1	K7ERK1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000161 AC: 18 AN: 1120480 Hom.: 0 Cov.: 31 AF XY: 0.0000169 AC XY: 9 AN XY: 532326

African (AFR) AF: 0.00 AC: 0 AN: 23982

American (AMR) AF: 0.00 AC: 0 AN: 10370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14640

East Asian (EAS) AF: 0.00 AC: 0 AN: 27952

South Asian (SAS) AF: 0.00 AC: 0 AN: 24010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4510

European-Non Finnish (NFE) AF: 0.0000193 AC: 18 AN: 933640

Other (OTH) AF: 0.00 AC: 0 AN: 44876

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 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	0.15
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.088
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.043	D
Polyphen		0.97	D
Vest4		0.096
MutPred		0.16		Loss of ubiquitination at K64 (P = 0.046)
MVP		0.55
MPC		0.74
ClinPred		0.83	D
GERP RS		3.8
PromoterAI		-0.049	Neutral
Varity_R		0.16
gMVP		0.45
Mutation Taster		=64/36	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: rs1157840967; hg19: chr19-10654942;