rs1554297905
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_005402.4(RALA):c.73G>A(p.Val25Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V25L) has been classified as Pathogenic.
Frequency
Consequence
NM_005402.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RALA | NM_005402.4 | c.73G>A | p.Val25Met | missense_variant | 2/5 | ENST00000005257.7 | |
RALA | XM_047420681.1 | c.73G>A | p.Val25Met | missense_variant | 2/5 | ||
RALA | XM_047420682.1 | c.73G>A | p.Val25Met | missense_variant | 3/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RALA | ENST00000005257.7 | c.73G>A | p.Val25Met | missense_variant | 2/5 | 1 | NM_005402.4 | P1 | |
RALA | ENST00000436179.1 | c.73G>A | p.Val25Met | missense_variant | 2/3 | 2 | |||
RALA | ENST00000434466.1 | c.55G>A | p.Val19Met | missense_variant, NMD_transcript_variant | 1/5 | 3 | |||
RALA | ENST00000468201.1 | n.262-9945G>A | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461816Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727216
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Mar 29, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RALA function (PMID: 30500825). 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) performed at Invitae indicates that this missense variant is expected to disrupt RALA protein function. ClinVar contains an entry for this variant (Variation ID: 521019). This missense change has been observed in individual(s) with RALA-related conditions (PMID: 30500825, 30761613). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 25 of the RALA protein (p.Val25Met). - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2019 | - - |
Hiatt-Neu-Cooper neurodevelopmental syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 06, 2021 | - - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at