chr4-122947396-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_145207.3(AFG2A):c.1622C>T(p.Pro541Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_145207.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPATA5 | ENST00000274008.5 | c.1622C>T | p.Pro541Leu | missense_variant | Exon 9 of 16 | 1 | NM_145207.3 | ENSP00000274008.3 | ||
SPATA5 | ENST00000422835.2 | n.1664C>T | non_coding_transcript_exon_variant | Exon 9 of 15 | 1 | |||||
SPATA5 | ENST00000675612.1 | c.1619C>T | p.Pro540Leu | missense_variant | Exon 9 of 17 | ENSP00000502453.1 | ||||
SPATA5 | ENST00000674886.1 | n.1684C>T | non_coding_transcript_exon_variant | Exon 9 of 11 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251432Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135884
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727234
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.1622C>T (p.P541L) alteration is located in exon 9 (coding exon 9) of the AFG2A gene. This alteration results from a C to T substitution at nucleotide position 1622, causing the proline (P) at amino acid position 541 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/251432) total alleles studied. The highest observed frequency was 0.015% (5/34590) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome Uncertain:1
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. This variant is present in population databases (rs143957561, ExAC 0.009%). This sequence change replaces proline with leucine at codon 541 of the SPATA5 protein (p.Pro541Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at