rs780025409

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_145207.3(AFG2A):c.1151T>C(p.Ile384Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000281 in 1,424,550 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

AFG2A
NM_145207.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.04

Publications

0 publications found

Variant links:

Genes affected

AFG2A (HGNC:18119): (AFG2 AAA ATPase homolog A) This gene encodes a member of the ATPase associated with diverse activities family, whose members are defined by a highly conserved ATPase domain. Members of this family participate in diverse cellular processes that include membrane fusion, DNA replication, microtubule severing, and protein degradation. The protein encoded by this gene has a putative mitochondrial targeting sequence and has been proposed to function in maintenance of mitochondrial function and integrity during mouse spermatogenesis. Allelic variants in this gene have been associated with epilepsy, hearing loss, and cognitive disability syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

AFG2A Gene-Disease associations (from GenCC):

microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia

AFG2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.46019 (below the threshold of 3.09). Trascript score misZ: 1.2041 (below the threshold of 3.09). GenCC associations: The gene is linked to microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3 link	c.1151T>C	p.Ile384Thr	missense_variant	Exon 6 of 16	ENST00000274008.5	NP_660208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AFG2A	ENST00000274008.5 link	c.1151T>C	p.Ile384Thr	missense_variant	Exon 6 of 16	1	NM_145207.3	ENSP00000274008.3
AFG2A	ENST00000422835.2 link	n.1193T>C		non_coding_transcript_exon_variant	Exon 6 of 15	1
AFG2A	ENST00000675612.1 link	c.1148T>C	p.Ile383Thr	missense_variant	Exon 6 of 17			ENSP00000502453.1
AFG2A	ENST00000674886.1 link	n.1213T>C		non_coding_transcript_exon_variant	Exon 6 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000436

AC:

AN:

229102

AF XY:

0.00000804

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000930

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1424550

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

707520

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31816

American (AMR)

AF:

0.00

AC:

AN:

36990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24424

East Asian (EAS)

AF:

0.00

AC:

AN:

39318

South Asian (SAS)

AF:

0.00

AC:

AN:

78130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

1097228

Other (OTH)

AF:

0.00

AC:

AN:

58694

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 05, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

Uncertain:1

Jul 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine with threonine at codon 384 of the SPATA5 protein (p.Ile384Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs780025409, ExAC 0.002%). This variant has not been reported in the literature in individuals with SPATA5-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

1.1

PhyloP100

7.0

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.98

Vest4

0.83

MutPred

0.59

Gain of relative solvent accessibility (P = 0.005);

MVP

0.96

MPC

0.52

ClinPred

0.99

GERP RS

5.1

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.77

gMVP

0.80

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over