rs1131692265

Variant names:

• chr6-106279773-T-A
• rs1131692265
• NM_004849.4:c.366A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_004849.4(ATG5):​c.366A>T​(p.Glu122Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATG5 NM_004849.4 missense
• Clinical Significance: no classifications from unflagged records no classifications from unflagged records P:1
• Conservation: PhyloP100: 3.54
• Publications: 17 publications found

Genes affected

ATG5 (HGNC:589): (autophagy related 5) The protein encoded by this gene, in combination with autophagy protein 12, functions as an E1-like activating enzyme in a ubiquitin-like conjugating system. The encoded protein is involved in several cellular processes, including autophagic vesicle formation, mitochondrial quality control after oxidative damage, negative regulation of the innate antiviral immune response, lymphocyte development and proliferation, MHC II antigen presentation, adipocyte differentiation, and apoptosis. Several transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Sep 2015]

ATG5 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 25

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 6-106279773-T-A is Pathogenic according to our data. Variant chr6-106279773-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 430932.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG5	NM_004849.4	MANE Select	c.366A>T	p.Glu122Asp	missense	Exon 5 of 8	NP_004840.1
	ATG5	NM_001286106.2		c.366A>T	p.Glu122Asp	missense	Exon 5 of 8	NP_001273035.1
	ATG5	NM_001286108.2		c.366A>T	p.Glu122Asp	missense	Exon 5 of 8	NP_001273037.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG5	ENST00000369076.8	TSL:1 MANE Select	c.366A>T	p.Glu122Asp	missense	Exon 5 of 8	ENSP00000358072.3
	ATG5	ENST00000343245.7	TSL:1	c.366A>T	p.Glu122Asp	missense	Exon 5 of 8	ENSP00000343313.3
	ATG5	ENST00000635758.2	TSL:1	c.132A>T	p.Glu44Asp	missense	Exon 4 of 7	ENSP00000490493.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: no classifications from unflagged records

Revision: no classifications from unflagged records

Pathogenic	VUS	Benign	Condition
1	-	-	Spinocerebellar ataxia, autosomal recessive 25 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.78		Gain of helix (P = 0.132)
MVP		0.76
MPC		1.6
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.58
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs1131692265; hg19: chr6-106727648;