chr17-8318795-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_173728.4(ARHGEF15):c.1918G>A(p.Glu640Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E640Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_173728.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARHGEF15 | NM_173728.4 | c.1918G>A | p.Glu640Lys | missense_variant | 12/16 | ENST00000361926.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARHGEF15 | ENST00000361926.8 | c.1918G>A | p.Glu640Lys | missense_variant | 12/16 | 1 | NM_173728.4 | P1 | |
ARHGEF15 | ENST00000421050.2 | c.1918G>A | p.Glu640Lys | missense_variant | 12/16 | 1 | P1 | ||
ARHGEF15 | ENST00000647883.1 | c.1381G>A | p.Glu461Lys | missense_variant | 9/13 | ||||
ARHGEF15 | ENST00000582060.1 | n.30G>A | non_coding_transcript_exon_variant | 1/2 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000520 AC: 13AN: 249994Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135472
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461278Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 726972
GnomAD4 genome AF: 0.000204 AC: 31AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74488
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 07, 2022 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 572173). This variant has not been reported in the literature in individuals affected with ARHGEF15-related conditions. This variant is present in population databases (rs375563358, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 640 of the ARHGEF15 protein (p.Glu640Lys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at