Genetic Variant NM_052936.5:c.929A>G (chrX-108150266-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_052936.5(ATG4A):c.929A>G(p.Asn310Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000182 in 1,098,228 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N310T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

ATG4A
NM_052936.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.76

Publications

0 publications found

Variant links:

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]

ATG4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.092063874).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATG4A	NM_052936.5	MANE Select	c.929A>G	p.Asn310Ser	missense	Exon 10 of 13	NP_443168.2
ATG4A	NM_178270.4		c.743A>G	p.Asn248Ser	missense	Exon 9 of 12	NP_840054.1	Q8WYN0-2
ATG4A	NM_001321287.2		c.698A>G	p.Asn233Ser	missense	Exon 11 of 14	NP_001308216.1	Q8WYN0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATG4A	ENST00000372232.8	TSL:1 MANE Select	c.929A>G	p.Asn310Ser	missense	Exon 10 of 13	ENSP00000361306.3	Q8WYN0-1
ATG4A	ENST00000345734.7	TSL:1	c.743A>G	p.Asn248Ser	missense	Exon 9 of 12	ENSP00000298131.5	Q8WYN0-2
ATG4A	ENST00000372246.7	TSL:1	n.*1087A>G		non_coding_transcript_exon	Exon 11 of 14	ENSP00000361320.3	F8W7J2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54143

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.00000237

AC:

AN:

842126

Other (OTH)

AF:

0.00

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.96

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.065

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

M_CAP

Benign

0.011

MetaRNN

Benign

0.092

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.17

PhyloP100

4.8

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.1

REVEL

Benign

0.084

Sift

Benign

0.98

Sift4G

Benign

0.96

Polyphen

0.0

Vest4

0.048

MutPred

0.31

Loss of catalytic residue at N310 (P = 0.0685)

MVP

0.45

MPC

0.31

ClinPred

0.14

GERP RS

4.5

Varity_R

0.31

gMVP

0.14

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over