chrX-108131267-G-T

Variant names:

• chrX-108131267-G-T
• rs146979084
• NM_052936.5:c.201G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_178271.3(ATG4A):​c.-31G>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 0.000681 in 1,209,479 control chromosomes in the GnomAD database, including 4 homozygotes. There are 222 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., 117 hem., cov: 23)
  • Exomes 𝑓: 0.00034 (2 hom. 105 hem.)
• Consequence: ATG4A NM_178271.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -5.31
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.111).
• BP6: Variant X-108131267-G-T is Benign according to our data. Variant chrX-108131267-G-T is described in ClinVar as Benign. ClinVar VariationId is 734035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178271.3. 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.201G>T	p.Thr67Thr	synonymous	Exon 4 of 13	NP_443168.2
	ATG4A	NM_001321287.2		c.-31G>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 14	NP_001308216.1	Q8WYN0-3
	ATG4A	NM_001321288.2		c.-31G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 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.201G>T	p.Thr67Thr	synonymous	Exon 4 of 13	ENSP00000361306.3	Q8WYN0-1
	ATG4A	ENST00000345734.7	TSL:1	c.201G>T	p.Thr67Thr	synonymous	Exon 4 of 12	ENSP00000298131.5	Q8WYN0-2
	ATG4A	ENST00000372246.7	TSL:1	n.*359G>T		non_coding_transcript_exon	Exon 5 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 447 AN: 112213 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.0000188

Gnomad OTH AF: 0.00333

GnomAD2 exomes AF: 0.00112 AC: 203 AN: 181311 AF XY: 0.000719

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00113

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: 0.000222

GnomAD4 exome AF: 0.000342 AC: 375 AN: 1097213 Hom.: 2 Cov.: 30 AF XY: 0.000289 AC XY: 105 AN XY: 362719

African (AFR) AF: 0.0111 AC: 293 AN: 26374

American (AMR) AF: 0.00102 AC: 36 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54035

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40526

Middle Eastern (MID) AF: 0.00104 AC: 4 AN: 3843

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841662

Other (OTH) AF: 0.000804 AC: 37 AN: 46039

GnomAD4 genome AF: 0.00400 AC: 449 AN: 112266 Hom.: 2 Cov.: 23 AF XY: 0.00340 AC XY: 117 AN XY: 34432

African (AFR) AF: 0.0137 AC: 425 AN: 30966

American (AMR) AF: 0.00170 AC: 18 AN: 10600

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53254

Other (OTH) AF: 0.00329 AC: 5 AN: 1522

Alfa AF: 0.000951 Hom.: 6

Bravo AF: 0.00429

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.10
DANN	Benign	0.71
PhyloP100		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=290/10	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: rs146979084; hg19: chrX-107374497; COSMIC: COSV100619694;