rs778493344
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005219.5(DIAPH1):āc.814C>Gā(p.Pro272Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000021 ( 0 hom. )
Consequence
DIAPH1
NM_005219.5 missense
NM_005219.5 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 3.79
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DIAPH1 | NM_005219.5 | c.814C>G | p.Pro272Ala | missense_variant | 8/28 | ENST00000389054.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIAPH1 | ENST00000389054.8 | c.814C>G | p.Pro272Ala | missense_variant | 8/28 | 5 | NM_005219.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249418Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135312
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461736Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727184
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GnomAD4 genome ? Cov.: 32
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32
ExAC
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1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 16, 2017 | The p.Pro272Ala variant in DIAPH1 has not been previously reported in individual s with hearing loss, but has been identified in 3/33580 Latino chromosomes by th e Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP r s778493344). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Pro272Ala variant is uncertain. - |
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 | Oct 04, 2023 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 272 of the DIAPH1 protein (p.Pro272Ala). This variant is present in population databases (rs778493344, gnomAD 0.009%). 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: 505416). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D;T;T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.;D;D;D
REVEL
Uncertain
Sift
Benign
T;.;.;T;T;T
Sift4G
Benign
T;.;T;T;T;T
Polyphen
D;.;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0672);Loss of disorder (P = 0.0672);.;.;Loss of disorder (P = 0.0672);.;
MVP
MPC
0.73
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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