2-219222875-T-C

Position:

• chr2-219222875-T-C

Variant summary

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

The NM_001077198.3(ATG9A):​c.1618A>G​(p.Thr540Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATG9A NM_001077198.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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 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.1618A>G	p.Thr540Ala	missense_variant	11/16	ENST00000361242.9	NP_001070666.1
ATG9A	NM_024085.5	c.1618A>G	p.Thr540Ala	missense_variant	10/15		NP_076990.4
ATG9A	NR_104255.2	n.1742A>G		non_coding_transcript_exon_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATG9A	ENST00000361242.9	c.1618A>G	p.Thr540Ala	missense_variant	11/16	2	NM_001077198.3	ENSP00000355173	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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

Dec 14, 2021

The c.1618A>G (p.T540A) alteration is located in exon 11 (coding exon 9) of the ATG9A gene. This alteration results from a A to G substitution at nucleotide position 1618, causing the threonine (T) at amino acid position 540 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	0.71
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T;T;T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	.;.;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.48	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.65	T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;.
Polyphen		0.98	D;D;D;.;.
Vest4		0.68
MutPred		0.43		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;.;
MVP		0.43
MPC		1.9
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr2-220087597;