chr4-123313915-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_145207.3(AFG2A):c.2533C>T(p.Leu845Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,453,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

AFG2A
NM_145207.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.06

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AFG2A	NM_145207.3 link	c.2533C>T	p.Leu845Phe	missense_variant	Exon 16 of 16	ENST00000274008.5	NP_660208.2	Q8NB90-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AFG2A	ENST00000274008.5 link	c.2533C>T	p.Leu845Phe	missense_variant	Exon 16 of 16	1	NM_145207.3	ENSP00000274008.3		Q8NB90-1
AFG2A	ENST00000675612.1 link	c.2602C>T	p.Leu868Phe	missense_variant	Exon 17 of 17			ENSP00000502453.1		A0A6Q8PGU6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000411

AC:

AN:

243446

AF XY:

0.00000761

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:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1453870

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722830

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33008

American (AMR)

AF:

0.00

AC:

AN:

42886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.00

AC:

AN:

83802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1109692

Other (OTH)

AF:

0.0000167

AC:

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 845 of the SPATA5 protein (p.Leu845Phe). This variant is present in population databases (rs777160273, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SPATA5-related conditions. ClinVar contains an entry for this variant (Variation ID: 575098). Advanced 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 at Invitae 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. 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

Benign

0.18

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.65

MetaSVM

Pathogenic

0.84

PhyloP100

6.1

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.74

Sift

Benign

0.036

Sift4G

Uncertain

0.043

Polyphen

0.95

Vest4

0.48

MVP

0.90

MPC

0.66

ClinPred

0.98

GERP RS

5.5

Varity_R

0.44

gMVP

0.39

Mutation Taster

=59/41

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

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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