10-93593823-C-T
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1PP2PP3_StrongBS1_Supporting
The NM_006744.4(RBP4):c.568G>A(p.Gly190Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000946 in 1,459,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_006744.4 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RBP4 | NM_006744.4 | c.568G>A | p.Gly190Ser | missense_variant, splice_region_variant | Exon 5 of 6 | ENST00000371464.8 | NP_006735.2 | |
RBP4 | NM_001323517.1 | c.568G>A | p.Gly190Ser | missense_variant, splice_region_variant | Exon 5 of 6 | NP_001310446.1 | ||
RBP4 | NM_001323518.2 | c.562G>A | p.Gly188Ser | missense_variant, splice_region_variant | Exon 5 of 6 | NP_001310447.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RBP4 | ENST00000371464.8 | c.568G>A | p.Gly190Ser | missense_variant, splice_region_variant | Exon 5 of 6 | 1 | NM_006744.4 | ENSP00000360519.3 | ||
RBP4 | ENST00000371467.5 | c.568G>A | p.Gly190Ser | missense_variant, splice_region_variant | Exon 5 of 6 | 5 | ENSP00000360522.1 | |||
RBP4 | ENST00000371469.2 | c.562G>A | p.Gly188Ser | missense_variant, splice_region_variant | Exon 5 of 6 | 5 | ENSP00000360524.2 | |||
FFAR4 | ENST00000604414.1 | c.697-10251C>T | intron_variant | Intron 2 of 2 | 3 | ENSP00000474477.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.0000120 AC: 3AN: 250478 AF XY: 0.0000148 show subpopulations
GnomAD4 exome AF: 0.0000946 AC: 138AN: 1459232Hom.: 0 Cov.: 32 AF XY: 0.0000909 AC XY: 66AN XY: 725988 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 190 of the RBP4 protein (p.Gly190Ser). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RBP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1413985). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at