rs200688040
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting
The NM_005219.5(DIAPH1):c.2800C>T(p.Arg934Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000967 in 1,613,808 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R934Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_005219.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DIAPH1 | NM_005219.5 | c.2800C>T | p.Arg934Trp | missense_variant | 22/28 | ENST00000389054.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIAPH1 | ENST00000389054.8 | c.2800C>T | p.Arg934Trp | missense_variant | 22/28 | 5 | NM_005219.5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000362 AC: 9AN: 248576Hom.: 0 AF XY: 0.0000445 AC XY: 6AN XY: 134976
GnomAD4 exome AF: 0.000101 AC: 147AN: 1461500Hom.: 0 Cov.: 32 AF XY: 0.000113 AC XY: 82AN XY: 727106
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74474
ClinVar
Submissions by phenotype
Autosomal dominant nonsyndromic hearing loss 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
DIAPH1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 17, 2024 | The DIAPH1 c.2800C>T variant is predicted to result in the amino acid substitution p.Arg934Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 934 of the DIAPH1 protein (p.Arg934Trp). This variant is present in population databases (rs200688040, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 573683). 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. 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