14-55369925-C-A

Variant names:

• chr14-55369925-C-A
• rs562870380
• NM_014924.5:c.1173G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014924.5(ATG14):​c.1173G>T​(p.Arg391Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000401 in 1,445,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R391R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: ATG14 NM_014924.5 missense, splice_region
• Scores: Splicing: ADA: 0.9971
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014924.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG14	NM_014924.5	MANE Select	c.1173G>T	p.Arg391Ser	missense splice_region	Exon 10 of 10	NP_055739.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG14	ENST00000247178.6	TSL:1 MANE Select	c.1173G>T	p.Arg391Ser	missense splice_region	Exon 10 of 10	ENSP00000247178.5	Q6ZNE5-1
	ATG14	ENST00000558189.1	TSL:2	n.1156G>T		splice_region non_coding_transcript_exon	Exon 7 of 7
	FBXO34	ENST00000681074.1		n.*653C>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000506304.1	Q9NWN3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000401 AC: 58 AN: 1445526 Hom.: 0 Cov.: 31 AF XY: 0.0000293 AC XY: 21 AN XY: 717518

African (AFR) AF: 0.00 AC: 0 AN: 32696

American (AMR) AF: 0.00 AC: 0 AN: 42306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25282

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.00 AC: 0 AN: 84918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.0000499 AC: 55 AN: 1102576

Other (OTH) AF: 0.0000504 AC: 3 AN: 59550

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.68		Loss of helix (P = 0.0033)
MVP		0.64
MPC		0.95
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.84
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs562870380; hg19: chr14-55836643;