rs376220834
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_005219.5(DIAPH1):c.3050T>C(p.Met1017Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000725 in 1,614,090 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1017I) has been classified as Uncertain significance.
Frequency
Consequence
NM_005219.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DIAPH1 | NM_005219.5 | c.3050T>C | p.Met1017Thr | missense_variant | 23/28 | ENST00000389054.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIAPH1 | ENST00000389054.8 | c.3050T>C | p.Met1017Thr | missense_variant | 23/28 | 5 | NM_005219.5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000394 AC: 60AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000762 AC: 19AN: 249484Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135350
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461892Hom.: 1 Cov.: 32 AF XY: 0.0000371 AC XY: 27AN XY: 727246
GnomAD4 genome ? AF: 0.000394 AC: 60AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74364
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 11, 2014 | Variant classified as Uncertain Significance - Favor Benign. The Met1017Thr vari ant in DIAPH1 has not been previously reported in individuals with hearing loss. It was identified in 0.025% (1/4022) of African American chromosomes by the NHL BI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The methionine (Met) at position 1017 is conserved in mammals, but not in birds or evolutionari ly distant species, with many bird species having a threonine. This raises the possibility that a change at this position may be tolerated. In summary, while t he clinical significance of the Met1017Thr variant is uncertain, these data sugg est that it is more likely to be benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 30, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
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 29, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1017 of the DIAPH1 protein (p.Met1017Thr). This variant is present in population databases (rs376220834, gnomAD 0.1%). 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: 178340). 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 tolerated. 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 12, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at