X-108137163-A-C

Position:

• chrX-108137163-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000372232.8(ATG4A):​c.540A>C​(p.Glu180Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,201,649 control chromosomes in the GnomAD database, including 50 homozygotes. There are 813 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., 348 hem., cov: 23)
  • Exomes 𝑓: 0.0016 (26 hom. 465 hem.)
• Consequence: ATG4A ENST00000372232.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.10

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020264179).
• BP6: Variant X-108137163-A-C is Benign according to our data. Variant chrX-108137163-A-C is described in ClinVar as [Benign]. Clinvar id is 791383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1270/112988) while in subpopulation AFR AF= 0.0377 (1174/31112). AF 95% confidence interval is 0.0359. There are 24 homozygotes in gnomad4. There are 348 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG4A	NM_052936.5	c.540A>C	p.Glu180Asp	missense_variant	7/13	ENST00000372232.8	NP_443168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG4A	ENST00000372232.8	c.540A>C	p.Glu180Asp	missense_variant	7/13	1	NM_052936.5	ENSP00000361306	P1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1266 AN: 112933 Hom.: 24 Cov.: 23 AF XY: 0.00989 AC XY: 347 AN XY: 35087

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00512

Gnomad ASJ AF: 0.000752

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000431

Gnomad OTH AF: 0.00980

GnomAD3 exomes AF: 0.00349 AC: 621 AN: 177862 Hom.: 9 AF XY: 0.00225 AC XY: 141 AN XY: 62668

Gnomad AFR exome AF: 0.0396

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.000817

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000438

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00157 AC: 1712 AN: 1088661 Hom.: 26 Cov.: 27 AF XY: 0.00131 AC XY: 465 AN XY: 354567

Gnomad4 AFR exome AF: 0.0410

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.000784

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000281

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000393

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome AF: 0.0112 AC: 1270 AN: 112988 Hom.: 24 Cov.: 23 AF XY: 0.00990 AC XY: 348 AN XY: 35152

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.00511

Gnomad4 ASJ AF: 0.000752

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000431

Gnomad4 OTH AF: 0.00968

Alfa AF: 0.00165 Hom.: 62

Bravo AF: 0.0136

ESP6500AA AF: 0.0347 AC: 133

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.00400 AC: 486

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L;.
MutationTaster	Benign	0.0000045	P;P;P;P
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.96	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.023	B;B;.
Vest4		0.24
MutPred		0.41		Gain of ubiquitination at K184 (P = 0.0985);Gain of ubiquitination at K184 (P = 0.0985);.;
MVP		0.64
MPC		1.1
ClinPred		0.039	T
GERP RS		3.7
Varity_R		0.52
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs79788197; hg19: chrX-107380393;