chr19-6494537-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_006087.4(TUBB4A):​c.*627A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 84,624 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 0.016 ( 0 hom., cov: 23)
Exomes 𝑓: 0.0037 ( 0 hom. )

Consequence

TUBB4A
NM_006087.4 3_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -2.06
Variant links:
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 -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0164 (1362/83010) while in subpopulation AFR AF= 0.0191 (413/21600). AF 95% confidence interval is 0.0176. There are 0 homozygotes in gnomad4. There are 648 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 1362 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TUBB4ANM_006087.4 linkuse as main transcriptc.*627A>C 3_prime_UTR_variant 4/4 ENST00000264071.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TUBB4AENST00000264071.7 linkuse as main transcriptc.*627A>C 3_prime_UTR_variant 4/41 NM_006087.4 P1
ENST00000596027.1 linkuse as main transcriptn.218T>G non_coding_transcript_exon_variant 1/25
ENST00000599292.1 linkuse as main transcriptn.194+24T>G intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0164
AC:
1361
AN:
82936
Hom.:
0
Cov.:
23
show subpopulations
Gnomad AFR
AF:
0.0192
Gnomad AMI
AF:
0.0254
Gnomad AMR
AF:
0.0139
Gnomad ASJ
AF:
0.0175
Gnomad EAS
AF:
0.00753
Gnomad SAS
AF:
0.0136
Gnomad FIN
AF:
0.0191
Gnomad MID
AF:
0.00962
Gnomad NFE
AF:
0.0158
Gnomad OTH
AF:
0.0176
GnomAD4 exome
AF:
0.00372
AC:
6
AN:
1614
Hom.:
0
Cov.:
0
AF XY:
0.00345
AC XY:
3
AN XY:
870
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00305
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00485
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0164
AC:
1362
AN:
83010
Hom.:
0
Cov.:
23
AF XY:
0.0165
AC XY:
648
AN XY:
39324
show subpopulations
Gnomad4 AFR
AF:
0.0191
Gnomad4 AMR
AF:
0.0138
Gnomad4 ASJ
AF:
0.0175
Gnomad4 EAS
AF:
0.00752
Gnomad4 SAS
AF:
0.0136
Gnomad4 FIN
AF:
0.0191
Gnomad4 NFE
AF:
0.0158
Gnomad4 OTH
AF:
0.0174
Alfa
AF:
0.178
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Torsion dystonia 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Hypomyelinating leukodystrophy 6 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.91
CADD
Benign
1.3
DANN
Benign
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1469859932; hg19: chr19-6494548; API