rs749129261

Variant names:

• chrX-108150266-A-C
• rs749129261
• NM_052936.5:c.929A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-108150266-A-C
• chrX-108150266-A-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_052936.5(ATG4A):​c.929A>C​(p.Asn310Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000355 in 1,210,774 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.000036 (0 hom. 13 hem.)
• Consequence: ATG4A NM_052936.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19262394).
• BS2: High Hemizygotes in GnomAd4 at 3 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.929A>C	p.Asn310Thr	missense	Exon 10 of 13	NP_443168.2
	ATG4A	NM_178270.4		c.743A>C	p.Asn248Thr	missense	Exon 9 of 12	NP_840054.1	Q8WYN0-2
	ATG4A	NM_001321287.2		c.698A>C	p.Asn233Thr	missense	Exon 11 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.929A>C	p.Asn310Thr	missense	Exon 10 of 13	ENSP00000361306.3	Q8WYN0-1
	ATG4A	ENST00000345734.7	TSL:1	c.743A>C	p.Asn248Thr	missense	Exon 9 of 12	ENSP00000298131.5	Q8WYN0-2
	ATG4A	ENST00000372246.7	TSL:1	n.*1087A>C		non_coding_transcript_exon	Exon 11 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112546 Hom.: 0 Cov.: 24

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: 0.0000751

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183369 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

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: 0.0000489

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000355 AC: 39 AN: 1098228 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 13 AN XY: 363586

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54143

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000451 AC: 38 AN: 842126

Other (OTH) AF: 0.0000217 AC: 1 AN: 46096

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112546 Hom.: 0 Cov.: 24 AF XY: 0.0000865 AC XY: 3 AN XY: 34700

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30944

American (AMR) AF: 0.00 AC: 0 AN: 10665

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3591

South Asian (SAS) AF: 0.00 AC: 0 AN: 2727

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6247

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53276

Other (OTH) AF: 0.00 AC: 0 AN: 1518

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000412 AC: 5

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	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.8
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.12
Sift	Benign	0.52	T
Sift4G	Benign	0.52	T
Polyphen		0.022	B
Vest4		0.26
MVP		0.60
MPC		0.44
ClinPred		0.29	T
GERP RS		4.5
Varity_R		0.50
gMVP		0.24
Mutation Taster		=85/15	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: rs749129261; hg19: chrX-107393496;