rs766034355

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_145207.3(AFG2A):c.1343C>T(p.Ser448Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,600,934 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 Pathogenic (★).

Frequency

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

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

AFG2A
NM_145207.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.28

Publications

2 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: Likely_pathogenic. The variant received 9 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, 0.946

PP5

Variant 4-122938134-C-T is Pathogenic according to our data. Variant chr4-122938134-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 203527.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3 link	c.1343C>T	p.Ser448Leu	missense_variant	Exon 8 of 16	ENST00000274008.5	NP_660208.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AFG2A	ENST00000274008.5 link	c.1343C>T	p.Ser448Leu	missense_variant	Exon 8 of 16	1	NM_145207.3	ENSP00000274008.3
AFG2A	ENST00000422835.2 link	n.1385C>T		non_coding_transcript_exon_variant	Exon 8 of 15	1
AFG2A	ENST00000675612.1 link	c.1340C>T	p.Ser447Leu	missense_variant	Exon 8 of 17			ENSP00000502453.1
AFG2A	ENST00000674886.1 link	n.1405C>T		non_coding_transcript_exon_variant	Exon 8 of 11

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000207

AC:

AN:

241752

AF XY:

0.00000767

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:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1448828

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

720106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32940

American (AMR)

AF:

0.00

AC:

AN:

42360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25784

East Asian (EAS)

AF:

0.00

AC:

AN:

39382

South Asian (SAS)

AF:

0.00

AC:

AN:

82474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1107034

Other (OTH)

AF:

0.00

AC:

AN:

59932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

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

AF:

0.0000197

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000180

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:2

Sep 03, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 448 of the SPATA5 protein (p.Ser448Leu). This variant is present in population databases (rs766034355, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of autosomal recessive epilepsy, hearing loss, and intellectual disability syndrome (EHLIDS) (PMID: 26299366, 29389922). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203527). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPATA5 protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.99

PhyloP100

7.3

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

0.68

Vest4

0.90

MutPred

0.74

Gain of catalytic residue at S448 (P = 0.0267);

MVP

0.89

MPC

0.54

ClinPred

0.91

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.84

gMVP

0.73

Mutation Taster

=31/69

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over