11-64895033-A-C

Position:

• chr11-64895033-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015104.3(ATG2A):​c.5757T>G​(p.Ile1919Met) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATG2A NM_015104.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32

Genes affected

ATG2A (HGNC:29028): (autophagy related 2A) Predicted to enable phosphatidylinositol-3-phosphate binding activity. Involved in autophagosome assembly. Predicted to be located in endoplasmic reticulum membrane; lipid droplet; and phagophore assembly site membrane. Predicted to be active in phagophore assembly site. Predicted to be extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG2A	NM_015104.3	c.5757T>G	p.Ile1919Met	missense_variant	41/41	ENST00000377264.8	NP_055919.2
ATG2A	NM_001367972.1	c.5739T>G	p.Ile1913Met	missense_variant	41/41		NP_001354901.1
ATG2A	NM_001367971.1	c.5733T>G	p.Ile1911Met	missense_variant	41/41		NP_001354900.1
ATG2A	XM_011544863.3	c.5763T>G	p.Ile1921Met	missense_variant	41/41		XP_011543165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG2A	ENST00000377264.8	c.5757T>G	p.Ile1919Met	missense_variant	41/41	1	NM_015104.3	ENSP00000366475.3
ATG2A	ENST00000418259.5	c.5166T>G	p.Ile1722Met	missense_variant	37/37	5		ENSP00000413716.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.5757T>G (p.I1919M) alteration is located in exon 41 (coding exon 41) of the ATG2A gene. This alteration results from a T to G substitution at nucleotide position 5757, causing the isoleucine (I) at amino acid position 1919 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.033	T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.86	D;T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.23
Sift	Uncertain	0.023	D;.
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.67		Gain of disorder (P = 0.023);.;
MVP		0.16
MPC		1.2
ClinPred		0.78	D
GERP RS		-2.4
Varity_R		0.22
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64662505;