4-122923143-A-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_145207.3(AFG2A):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,614,182 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

AFG2A
NM_145207.3 initiator_codon

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:2

Conservation

PhyloP100: 3.39

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 links:

NUDT6 (HGNC:8053): (nudix hydrolase 6) This gene overlaps and lies on the opposite strand from FGF2 gene, and is thought to be the FGF2 antisense gene. The two genes are independently transcribed, and their expression shows an inverse relationship, suggesting that this antisense transcript may regulate FGF2 expression. This gene has also been shown to have hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF2 expression. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

NUDT6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 75 codons. Genomic position: 122927693. Lost 0.083 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-122923143-A-C is Pathogenic according to our data. Variant chr4-122923143-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203533.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=2}. Variant chr4-122923143-A-C is described in Lovd as [Likely_pathogenic]. Variant chr4-122923143-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 16	ENST00000274008.5	NP_660208.2	Q8NB90-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATA5	ENST00000274008.5 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 16	1	NM_145207.3	ENSP00000274008.3		Q8NB90-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152186

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251382

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135858

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:

0.000185

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

727240

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:

0.000140

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000105

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000761

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 08, 2017

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported with a de novo missense variant on the opposite allele (in trans) in a male with features of a SPATA5-related disorder who underwent trio-based whole exome sequencing (Papuc et al., 2019); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30552426) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AFG2A: PM2, PM3, PVS1:Moderate -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Pathogenic:2Uncertain:1

May 06, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the SPATA5 mRNA. The next in-frame methionine is located at codon 75. This variant is present in population databases (rs552219028, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 30552426). ClinVar contains an entry for this variant (Variation ID: 203533). 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. -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (MIM#616577). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 27 heterozygotes, 0 homozygotes). (SP) 0311 - Multiple alternative nucleotide changes at the initiation codon are present in gnomAD (highest allele count in v2: 5 heterozygotes, 0 homozygotes). (I) 0710 - Other variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. c.1A>T and c.1A>G are predicted to result in a loss of the canonical translation initiation codon, and have been reported as VUS by a clinical testing laboratory in individuals without a second variant that is pathogenic, likely pathogenic or VUS in SPATA5 (ClinVar, personal communication). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as compound heterozygous in two affected individuals, one with encephalopathy and seizures, the other with clinical features including global developmental delay and hearing impairment (PMID: 30552426, DDD study). This variant has also been reported by multiple clinical testing laboratories as likely pathogenic or pathogenic (ClinVar). In addition, it has been reported as a VUS by a clinical testing laboratory in individuals without a second variant that is pathogenic, likely pathogenic or VUS in SPATA5 (ClinVar, personal communication). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not specified

Uncertain:1

Mar 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SPATA5 c.1A>C (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream in-frame Met is found at codon 75. No non-NMD-causing variants upstream of this codon have been classified as pathogenic. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251382 control chromosomes (gnomAD). c.1A>C has been reported in the literature in an individual affected with early-onset epileptic encephalopathy (Papuc_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30552426). ClinVar contains an entry for this variant (Variation ID: 203533). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.60

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.010

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.82

PROVEAN

Benign

-0.58

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.52

Vest4

0.76

MutPred

0.99

Gain of glycosylation at S2 (P = 8e-04);

MVP

0.93

ClinPred

0.98

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.24

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