2-219223590-G-C

Position:

• chr2-219223590-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001077198.3(ATG9A):​c.1594C>G​(p.Pro532Ala) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATG9A NM_001077198.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.88

Genes affected

ATG9A (HGNC:22408): (autophagy related 9A) Acts upstream of or within autophagosome assembly. Located in endosome; phagophore assembly site; and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG9A	NM_001077198.3	c.1594C>G	p.Pro532Ala	missense_variant	10/16	ENST00000361242.9	NP_001070666.1
ATG9A	NM_024085.5	c.1594C>G	p.Pro532Ala	missense_variant	9/15		NP_076990.4
ATG9A	NR_104255.2	n.1718C>G		non_coding_transcript_exon_variant	10/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG9A	ENST00000361242.9	c.1594C>G	p.Pro532Ala	missense_variant	10/16	2	NM_001077198.3	ENSP00000355173.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

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

May 30, 2024

The c.1594C>G (p.P532A) alteration is located in exon 10 (coding exon 8) of the ATG9A gene. This alteration results from a C to G substitution at nucleotide position 1594, causing the proline (P) at amino acid position 532 to be replaced by an alanine (A). 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	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;D;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.027	D;D;D;D;D
Sift4G	Uncertain	0.040	D;D;D;D;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.65
MutPred		0.81		Loss of disorder (P = 0.0911);Loss of disorder (P = 0.0911);Loss of disorder (P = 0.0911);.;.;
MVP		0.36
MPC		2.1
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.48
gMVP		0.73

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: chr2-220088312;