rs118102196
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_006087.4(TUBB4A):c.921C>T(p.His307=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,613,948 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.015 ( 24 hom., cov: 32)
Exomes 𝑓: 0.021 ( 405 hom. )
Consequence
TUBB4A
NM_006087.4 synonymous
NM_006087.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.938
Genes affected
TUBB4A (HGNC:20774): (tubulin beta 4A class IVa) This gene encodes a member of the beta tubulin family. Beta tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene cause hypomyelinating leukodystrophy-6 and autosomal dominant torsion dystonia-4. Alternate splicing results in multiple transcript variants encoding different isoforms. A pseudogene of this gene is found on chromosome X. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.57).
BP6
?
Variant 19-6495578-G-A is Benign according to our data. Variant chr19-6495578-G-A is described in ClinVar as [Benign]. Clinvar id is 240288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6495578-G-A is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.938 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0149 (2272/152338) while in subpopulation NFE AF= 0.0239 (1623/68020). AF 95% confidence interval is 0.0229. There are 24 homozygotes in gnomad4. There are 998 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 2272 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TUBB4A | NM_006087.4 | c.921C>T | p.His307= | synonymous_variant | 4/4 | ENST00000264071.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TUBB4A | ENST00000264071.7 | c.921C>T | p.His307= | synonymous_variant | 4/4 | 1 | NM_006087.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0150 AC: 2276AN: 152220Hom.: 24 Cov.: 32
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GnomAD3 exomes AF: 0.0164 AC: 4102AN: 250082Hom.: 44 AF XY: 0.0167 AC XY: 2266AN XY: 135374
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GnomAD4 exome AF: 0.0211 AC: 30774AN: 1461610Hom.: 405 Cov.: 32 AF XY: 0.0207 AC XY: 15069AN XY: 727140
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GnomAD4 genome ? AF: 0.0149 AC: 2272AN: 152338Hom.: 24 Cov.: 32 AF XY: 0.0134 AC XY: 998AN XY: 74496
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypomyelinating leukodystrophy 6 Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Torsion dystonia 4 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
TUBB4A-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 30, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
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