5-141573496-G-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting
The NM_005219.5(DIAPH1):c.2354C>T(p.Ser785Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,610,166 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 (★).
Frequency
Genomes: 𝑓 0.000040 ( 0 hom., cov: 28)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
DIAPH1
NM_005219.5 missense
NM_005219.5 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 3.39
Genes affected
DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.27041766).
BS2
High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DIAPH1 | NM_005219.5 | c.2354C>T | p.Ser785Phe | missense_variant | 16/28 | ENST00000389054.8 | NP_005210.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DIAPH1 | ENST00000389054.8 | c.2354C>T | p.Ser785Phe | missense_variant | 16/28 | 5 | NM_005219.5 | ENSP00000373706.4 | ||
DIAPH1 | ENST00000518047.5 | c.2327C>T | p.Ser776Phe | missense_variant | 15/27 | 5 | ENSP00000428268.2 | |||
DIAPH1 | ENST00000647433.1 | c.2354C>T | p.Ser785Phe | missense_variant | 16/29 | ENSP00000494675.1 |
Frequencies
GnomAD3 genomes AF: 0.0000396 AC: 6AN: 151678Hom.: 0 Cov.: 28
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GnomAD3 exomes AF: 0.00000811 AC: 2AN: 246732Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134344
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458382Hom.: 0 Cov.: 39 AF XY: 0.00000138 AC XY: 1AN XY: 725440
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GnomAD4 genome AF: 0.0000395 AC: 6AN: 151784Hom.: 0 Cov.: 28 AF XY: 0.0000270 AC XY: 2AN XY: 74154
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
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 | Labcorp Genetics (formerly Invitae), Labcorp | May 10, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 572032). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. This variant is present in population databases (rs532205362, gnomAD 0.02%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 785 of the DIAPH1 protein (p.Ser785Phe). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;D;D;D
REVEL
Benign
Sift
Benign
D;.;.;D;D;D
Sift4G
Uncertain
D;.;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Gain of methylation at K786 (P = 0.0409);Gain of methylation at K786 (P = 0.0409);.;.;Gain of methylation at K786 (P = 0.0409);.;
MVP
MPC
0.57
ClinPred
D
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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