chr5-141524167-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_005219.5(DIAPH1):c.3637C>T(p.Arg1213*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,874 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 Pathogenic (★★).
Frequency
Consequence
NM_005219.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DIAPH1 | ENST00000389054.8 | c.3637C>T | p.Arg1213* | stop_gained | Exon 27 of 28 | 5 | NM_005219.5 | ENSP00000373706.4 | ||
DIAPH1 | ENST00000518047.5 | c.3610C>T | p.Arg1204* | stop_gained | Exon 26 of 27 | 5 | ENSP00000428268.2 | |||
DIAPH1 | ENST00000647433.1 | c.3637C>T | p.Arg1213* | stop_gained | Exon 27 of 29 | ENSP00000494675.1 | ||||
DIAPH1 | ENST00000468119.3 | c.43C>T | p.Arg15* | stop_gained | Exon 2 of 3 | 4 | ENSP00000493546.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461874Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727238
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Identified in multiple unrelated individuals with autosomal dominant sensorineural hearing loss in published literature; thrombocytopenia was also reported in several families (PMID: 28983057, 27911912, 26912466, 27808407, 27707755); Published functional studies demonstrate the p.(R1213X) variant causes increased activity as compared to wild-type (PMID: 26912466, 27707755); Nonsense variant predicted to result in protein truncation as the last 60 amino acids are lost; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27808407, 37543941, 34232383, 27707755, 29985732, 27911912, 28815995, 31152317, 31473629, 32594080, 34223798, 28983057, 26912466) -
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Autosomal dominant nonsyndromic hearing loss 1 Pathogenic:2
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Rare genetic deafness Pathogenic:1
The p.Arg1213X variant in DIAPH1 has been reported in six probands with either h earing loss or hearing loss with thrombocytopenia and segregated in 10 affected family members (Iwasa 2016, Stritt 2016, Ueyama 2016, Neuhaus 2017). This varian t was absent from large population studies. A mouse model expressing the p.Arg12 13X variant exhibited progressive hearing loss and loss of inner and outer hair cells. Homozygous mice exhibited an exacerbated hearing loss (Ueyama 2016). Addi tional studies performed in transfected cells indicate that this variant may res ult in constitutive activation of the DIAPH1 protein, a member of the formin pro tein family, which nucleate and elongate actin (Ueyama 2016). Furthermore, cultu red megakaryocytes from patients harboring p.Arg1213X showed reduced proplatelet formation, cell clustering and abnormal cortical filamentous actin, and platele ts had increased actin and stable microtubules. RT-PCR performed on samples from 2 probands showed presence of both wild-type and Arg1213X mRNA, suggesting that the DIAPH1 is prematurely truncated. Collectively, the functional evidence sugg ests either a gain-of-function or dominant negative effect. In summary, this var iant meets criteria to be classified as pathogenic for autosomal dominant hearin g loss with thrombocytopenia. ACMG/AMP criteria applied: PS3, PP1_Strong, PM2, P S4_Moderate. -
Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg1213*) in the DIAPH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the DIAPH1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal dominant hearing loss with or without macrothrombocytopenia (PMID: 26912466, 27707755, 27808407, 27911912, 28815995, 28983057). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3610C>T (R1204X). ClinVar contains an entry for this variant (Variation ID: 228577). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DIAPH1 function leading to constitutive activation for gain-of-function (PMID: 26912466, 27707755, 32678080). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at