2-219222102-A-T

Position:

• chr2-219222102-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001077198.3(ATG9A):​c.2093T>A​(p.Leu698Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.21

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]

ENSG00000284820 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATG9A	NM_001077198.3	c.2093T>A	p.Leu698Gln	missense_variant	13/16	ENST00000361242.9	NP_001070666.1
ATG9A	NM_024085.5	c.2093T>A	p.Leu698Gln	missense_variant	12/15		NP_076990.4
ATG9A	NR_104255.2	n.2217T>A		non_coding_transcript_exon_variant	13/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG9A	ENST00000361242.9	c.2093T>A	p.Leu698Gln	missense_variant	13/16	2	NM_001077198.3	ENSP00000355173.4
ENSG00000284820	ENST00000446716.5	n.338T>A		non_coding_transcript_exon_variant	3/22	2		ENSP00000398528.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Aug 01, 2024

The c.2093T>A (p.L698Q) alteration is located in exon 13 (coding exon 11) of the ATG9A gene. This alteration results from a T to A substitution at nucleotide position 2093, causing the leucine (L) at amino acid position 698 to be replaced by a glutamine (Q). 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	0.31
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T;T;T;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	2.0	M;M;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.38	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.92
MutPred		0.35		Gain of disorder (P = 0.0384);Gain of disorder (P = 0.0384);Gain of disorder (P = 0.0384);.;
MVP		0.51
MPC		0.43
ClinPred		0.66	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.48

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: rs1950772992; hg19: chr2-220086824;