Genetic Variant ATG14:p.Arg492His (chr14-55369623-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014924.5(ATG14):c.1475G>A(p.Arg492His) variant causes a missense change. The variant allele was found at a frequency of 0.0000191 in 1,514,396 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ATG14
NM_014924.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02

Variant links:

Genes affected

ATG14 (HGNC:19962): (autophagy related 14) Enables GTPase binding activity. Involved in several processes, including macroautophagy; regulation of phosphorylation; and response to mitochondrial depolarisation. Acts upstream of or within endosome to lysosome transport. Located in autophagosome and phagophore assembly site membrane. Is extrinsic component of omegasome membrane and extrinsic component of phagophore assembly site membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATG14 links:

FBXO34 (HGNC:20201): (F-box protein 34) Members of the F-box protein family, such as FBXO34, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

FBXO34 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ATG14	NM_014924.5 link	c.1475G>A	p.Arg492His	missense_variant	Exon 10 of 10	ENST00000247178.6	NP_055739.2	Q6ZNE5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATG14	ENST00000247178.6 link	c.1475G>A	p.Arg492His	missense_variant	Exon 10 of 10	1	NM_014924.5	ENSP00000247178.5	Q6ZNE5-1
ATG14	ENST00000558189.1 link	n.1458G>A		non_coding_transcript_exon_variant	Exon 7 of 7	2
FBXO34	ENST00000681074.1 link	n.*589-238C>T		intron_variant	Intron 4 of 4			ENSP00000506304.1	Q9NWN3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000434

AC:

AN:

184350

Hom.:

AF XY:

0.0000618

AC XY:

AN XY:

97122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000900

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000191

AC:

AN:

1362190

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

666498

show subpopulations

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:

0.0000235

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000665

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1475G>A (p.R492H) alteration is located in exon 10 (coding exon 10) of the ATG14 gene. This alteration results from a G to A substitution at nucleotide position 1475, causing the arginine (R) at amino acid position 492 to be replaced by a histidine (H). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.028

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.4

REVEL

Benign

0.25

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.69

MutPred

0.54

Loss of MoRF binding (P = 0.0495);

MVP

0.58

MPC

1.1

ClinPred

0.50

GERP RS

5.1

Varity_R

0.26

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over