rs200506473
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_ModerateBP6_Very_StrongBP7BS1BS2_Supporting
The NM_005219.5(DIAPH1):c.1659G>A(p.Lys553=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,080 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 Likely benign (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
DIAPH1
NM_005219.5 synonymous
NM_005219.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.556
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 Benign. Variant got -16 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.37).
BP6
?
Variant 5-141574191-C-T is Benign according to our data. Variant chr5-141574191-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
Synonymous conserved (PhyloP=0.556 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000554 (81/1461850) while in subpopulation AMR AF= 0.00174 (78/44722). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4_exome. There are 35 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 8 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 | UniProt |
---|---|---|---|---|---|---|---|
DIAPH1 | NM_005219.5 | c.1659G>A | p.Lys553= | synonymous_variant | 16/28 | ENST00000389054.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIAPH1 | ENST00000389054.8 | c.1659G>A | p.Lys553= | synonymous_variant | 16/28 | 5 | NM_005219.5 | A2 | |
DIAPH1 | ENST00000518047.5 | c.1632G>A | p.Lys544= | synonymous_variant | 15/27 | 5 | P4 | ||
DIAPH1 | ENST00000647433.1 | c.1659G>A | p.Lys553= | synonymous_variant | 16/29 | A2 | |||
DIAPH1 | ENST00000647330.1 | c.*886G>A | 3_prime_UTR_variant, NMD_transcript_variant | 15/15 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152112Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000309 AC: 77AN: 249506Hom.: 0 AF XY: 0.000222 AC XY: 30AN XY: 135370
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GnomAD4 exome AF: 0.0000554 AC: 81AN: 1461850Hom.: 0 Cov.: 36 AF XY: 0.0000481 AC XY: 35AN XY: 727222
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152230Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74428
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 23, 2017 | p.Lys553Lys in exon 16 of DIAPH1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.26% (30/11552) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200506473). - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2020 | - - |
Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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