X-108150219-G-A

Variant names:

• chrX-108150219-G-A
• rs34691372
• NM_052936.5:c.882G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_052936.5(ATG4A):​c.882G>A​(p.Thr294Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,210,278 control chromosomes in the GnomAD database, including 174 homozygotes. There are 1,623 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (89 hom., 785 hem., cov: 23)
  • Exomes 𝑓: 0.0028 (85 hom. 838 hem.)
• Consequence: ATG4A NM_052936.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.15

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.042).
• BP6: Variant X-108150219-G-A is Benign according to our data. Variant chrX-108150219-G-A is described in ClinVar as [Benign]. Clinvar id is 769183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATG4A	NM_052936.5	c.882G>A	p.Thr294Thr	synonymous_variant	Exon 10 of 13	ENST00000372232.8	NP_443168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATG4A	ENST00000372232.8	c.882G>A	p.Thr294Thr	synonymous_variant	Exon 10 of 13	1	NM_052936.5	ENSP00000361306.3

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 2888 AN: 112196 Hom.: 89 Cov.: 23

Gnomad AFR AF: 0.0894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000736

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00790 AC: 1450 AN: 183457 AF XY: 0.00524

Gnomad AFR exome AF: 0.0976

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00284 AC: 3116 AN: 1098029 Hom.: 85 Cov.: 31 AF XY: 0.00231 AC XY: 838 AN XY: 363389

Gnomad4 AFR exome AF: 0.0951 AC: 2509 AN: 26394

Gnomad4 AMR exome AF: 0.00562 AC: 198 AN: 35207

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19385

Gnomad4 EAS exome AF: 0.0000331 AC: 1 AN: 30205

Gnomad4 SAS exome AF: 0.000296 AC: 16 AN: 54142

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40534

Gnomad4 NFE exome AF: 0.000112 AC: 94 AN: 841937

Gnomad4 Remaining exome AF: 0.00610 AC: 281 AN: 46088

GnomAD4 genome AF: 0.0258 AC: 2895 AN: 112249 Hom.: 89 Cov.: 23 AF XY: 0.0228 AC XY: 785 AN XY: 34433

Gnomad4 AFR AF: 0.0894 AC: 0.0894486 AN: 0.0894486

Gnomad4 AMR AF: 0.00967 AC: 0.00967409 AN: 0.00967409

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000369 AC: 0.000369413 AN: 0.000369413

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000263 AC: 0.000263019 AN: 0.000263019

Gnomad4 OTH AF: 0.0138 AC: 0.0137615 AN: 0.0137615

Alfa AF: 0.0115 Hom.: 77

Bravo AF: 0.0306

EpiCase AF: 0.000654

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 25, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.29
DANN	Uncertain	0.99
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs34691372; hg19: chrX-107393449;