rs188786829

Variant names:

• chrX-108137978-T-C
• rs188786829
• NM_052936.5:c.722T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_052936.5(ATG4A):​c.722T>C​(p.Val241Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,199,653 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 279 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V241G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., 15 hem., cov: 23)
  • Exomes 𝑓: 0.00076 (0 hom. 264 hem.)
• Consequence: ATG4A NM_052936.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0262793).
• BS2: High Hemizygotes in GnomAd4 at 15 gene

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.722T>C	p.Val241Ala	missense	Exon 8 of 13	NP_443168.2
	ATG4A	NM_001321287.2		c.491T>C	p.Val164Ala	missense	Exon 9 of 14	NP_001308216.1	Q8WYN0-3
	ATG4A	NM_001321288.2		c.491T>C	p.Val164Ala	missense	Exon 8 of 13	NP_001308217.1	Q8WYN0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG4A	ENST00000372232.8	TSL:1 MANE Select	c.722T>C	p.Val241Ala	missense	Exon 8 of 13	ENSP00000361306.3	Q8WYN0-1
	ATG4A	ENST00000345734.7	TSL:1	c.628+94T>C		intron	N/A	ENSP00000298131.5	Q8WYN0-2
	ATG4A	ENST00000372246.7	TSL:1	n.*880T>C		non_coding_transcript_exon	Exon 9 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 52 AN: 111266 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000669

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00116

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000622

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.000781 AC: 133 AN: 170298 AF XY: 0.000990

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.000728

Gnomad ASJ exome AF: 0.000159

Gnomad EAS exome AF: 0.0000735

Gnomad FIN exome AF: 0.00105

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.000757 AC: 824 AN: 1088333 Hom.: 0 Cov.: 31 AF XY: 0.000743 AC XY: 264 AN XY: 355229

African (AFR) AF: 0.00 AC: 0 AN: 26265

American (AMR) AF: 0.000784 AC: 27 AN: 34438

Ashkenazi Jewish (ASJ) AF: 0.000107 AC: 2 AN: 18710

East Asian (EAS) AF: 0.00 AC: 0 AN: 30113

South Asian (SAS) AF: 0.0000193 AC: 1 AN: 51733

European-Finnish (FIN) AF: 0.000797 AC: 32 AN: 40141

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4076

European-Non Finnish (NFE) AF: 0.000878 AC: 735 AN: 837157

Other (OTH) AF: 0.000569 AC: 26 AN: 45700

GnomAD4 genome AF: 0.000467 AC: 52 AN: 111320 Hom.: 0 Cov.: 23 AF XY: 0.000447 AC XY: 15 AN XY: 33524

African (AFR) AF: 0.0000654 AC: 2 AN: 30589

American (AMR) AF: 0.000668 AC: 7 AN: 10480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.000283 AC: 1 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2598

European-Finnish (FIN) AF: 0.00116 AC: 7 AN: 6013

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000622 AC: 33 AN: 53041

Other (OTH) AF: 0.00132 AC: 2 AN: 1520

Alfa AF: 0.00126 Hom.: 40

Bravo AF: 0.000438

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.000898 AC: 109

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	0.18
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.087
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.098
MVP		0.45
MPC		0.48
ClinPred		0.015	T
GERP RS		5.4
Varity_R		0.17
gMVP		0.46
Mutation Taster		=74/26	polymorphism (auto)

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: rs188786829; hg19: chrX-107381208; COSMIC: COSV58966699;