rs782580975
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_001353921.2(ARHGEF9):c.1488G>A(p.Ser496=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,206,575 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., 5 hem., cov: 22)
Exomes 𝑓: 0.00013 ( 0 hom. 42 hem. )
Consequence
ARHGEF9
NM_001353921.2 synonymous
NM_001353921.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.45
Genes affected
ARHGEF9 (HGNC:14561): (Cdc42 guanine nucleotide exchange factor 9) The protein encoded by this gene is a Rho-like GTPase that switches between the active (GTP-bound) state and inactive (GDP-bound) state to regulate CDC42 and other genes. This brain-specific protein also acts as an adaptor protein for the recruitment of gephyrin and together these proteins facilitate receceptor recruitement in GABAnergic and glycinergic synapses. Defects in this gene are the cause of startle disease with epilepsy (STHEE), also known as hyperekplexia with epilepsy, as well as several other types of cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
?
Variant X-63638112-C-T is Benign according to our data. Variant chrX-63638112-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 465078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-63638112-C-T is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=-1.45 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000144 (16/111098) while in subpopulation AMR AF= 0.000578 (6/10389). AF 95% confidence interval is 0.000251. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd4 at 5 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARHGEF9 | NM_001353921.2 | c.1488G>A | p.Ser496= | synonymous_variant | 10/10 | ENST00000671741.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARHGEF9 | ENST00000671741.2 | c.1488G>A | p.Ser496= | synonymous_variant | 10/10 | NM_001353921.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000144 AC: 16AN: 111052Hom.: 0 Cov.: 22 AF XY: 0.000150 AC XY: 5AN XY: 33268
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GnomAD3 exomes AF: 0.000125 AC: 22AN: 176384Hom.: 0 AF XY: 0.0000814 AC XY: 5AN XY: 61442
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GnomAD4 exome AF: 0.000131 AC: 143AN: 1095477Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 42AN XY: 360999
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GnomAD4 genome ? AF: 0.000144 AC: 16AN: 111098Hom.: 0 Cov.: 22 AF XY: 0.000150 AC XY: 5AN XY: 33324
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ClinVar
Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 31, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 23, 2020 | - - |
Developmental and epileptic encephalopathy, 8 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at