Variant 19-6494537-T-G details in Genebe, Genetics Data Aggregator

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

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

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]

TUBB4A links:

(HGNC:):

links:

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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
TUBB4A	NM_006087.4 linkuse as main transcript	c.*627A>C		3_prime_UTR_variant	4/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris
TUBB4A	ENST00000264071.7 linkuse as main transcript	c.*627A>C	3_prime_UTR_variant	4/4	1	NM_006087.4	P1
	ENST00000596027.1 linkuse as main transcript	n.218T>G	non_coding_transcript_exon_variant	1/2	5
	ENST00000599292.1 linkuse as main transcript	n.194+24T>G	intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

1361

AN:

82936

Hom.:

Cov.:

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:

AN:

1614

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

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.:

Cov.:

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Torsion dystonia 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over