chr4-122923207-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145207.3(SPATA5):ā€‹c.65C>Gā€‹(p.Ser22Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

SPATA5
NM_145207.3 missense

Scores

5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.457
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09724885).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPATA5NM_145207.3 linkuse as main transcriptc.65C>G p.Ser22Cys missense_variant 1/16 ENST00000274008.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AFG2AENST00000274008.5 linkuse as main transcriptc.65C>G p.Ser22Cys missense_variant 1/161 NM_145207.3 P1Q8NB90-1
AFG2AENST00000422835.2 linkuse as main transcriptn.107C>G non_coding_transcript_exon_variant 1/151
AFG2AENST00000675612.1 linkuse as main transcriptc.65C>G p.Ser22Cys missense_variant 1/17
AFG2AENST00000674886.1 linkuse as main transcriptn.130C>G non_coding_transcript_exon_variant 1/11

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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
Uncertain significance, criteria provided, single submitterclinical testingInvitaeApr 16, 2018This sequence change replaces serine with cysteine at codon 22 of the SPATA5 protein (p.Ser22Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). 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 output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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
Benign
0.086
BayesDel_addAF
Uncertain
0.048
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
12
DANN
Uncertain
0.98
DEOGEN2
Benign
0.012
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.027
N
LIST_S2
Benign
0.32
T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.097
T
MetaSVM
Uncertain
-0.15
T
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.98
N
REVEL
Benign
0.13
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.0040
D
Polyphen
0.0020
B
Vest4
0.20
MutPred
0.24
Gain of glycosylation at S25 (P = 0.0175);
MVP
0.53
MPC
0.14
ClinPred
0.15
T
GERP RS
1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.17

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.

Other links and lift over

dbSNP: rs1560780127; hg19: chr4-123844362; COSMIC: COSV56782397; COSMIC: COSV56782397; API