rs1194604609

Variant names:

• chrX-108137806-A-C
• rs1194604609
• NM_052936.5:c.550A>C

Variant summary

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

The NM_052936.5(ATG4A):​c.550A>C​(p.Lys184Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000963 in 1,038,452 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: ATG4A NM_052936.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

Genes affected

ATG4A (HGNC:16489): (autophagy related 4A 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 encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. [provided by RefSeq, Mar 2016]

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=0.33130318).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052936.5. 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
	ATG4A	NM_052936.5	MANE Select	c.550A>C	p.Lys184Gln	missense splice_region	Exon 8 of 13	NP_443168.2
	ATG4A	NM_178270.4		c.550A>C	p.Lys184Gln	missense splice_region	Exon 8 of 12	NP_840054.1	Q8WYN0-2
	ATG4A	NM_001321287.2		c.319A>C	p.Lys107Gln	missense splice_region	Exon 9 of 14	NP_001308216.1	Q8WYN0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4A	ENST00000372232.8	TSL:1 MANE Select	c.550A>C	p.Lys184Gln	missense splice_region	Exon 8 of 13	ENSP00000361306.3	Q8WYN0-1
	ATG4A	ENST00000345734.7	TSL:1	c.550A>C	p.Lys184Gln	missense splice_region	Exon 8 of 12	ENSP00000298131.5	Q8WYN0-2
	ATG4A	ENST00000372246.7	TSL:1	n.*708A>C		splice_region non_coding_transcript_exon	Exon 9 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000750 AC: 1 AN: 133253 AF XY: 0.00

Gnomad AFR exome AF: 0.0000811

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.63e-7 AC: 1 AN: 1038452 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 332566

African (AFR) AF: 0.0000417 AC: 1 AN: 24004

American (AMR) AF: 0.00 AC: 0 AN: 24214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15490

East Asian (EAS) AF: 0.00 AC: 0 AN: 29585

South Asian (SAS) AF: 0.00 AC: 0 AN: 44112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38309

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3841

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 815450

Other (OTH) AF: 0.00 AC: 0 AN: 43447

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

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	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.080	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.17
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.051	B
Vest4		0.41
MutPred		0.51		Loss of ubiquitination at K184 (P = 0.0183)
MVP		0.51
MPC		1.2
ClinPred		0.36	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.55
Mutation Taster		=66/34	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: rs1194604609; hg19: chrX-107381036;