Variant chr19-6494735-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_006087.4(TUBB4A):c.*429C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 222,072 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 4 hom., cov: 30)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

TUBB4A
NM_006087.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.209

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 19-6494735-G-A is Benign according to our data. Variant chr19-6494735-G-A is described in ClinVar as [Benign]. Clinvar id is 330253.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00352 (536/152060) while in subpopulation AFR AF= 0.0119 (494/41436). AF 95% confidence interval is 0.0111. There are 4 homozygotes in gnomad4. There are 247 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 536 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4 linkuse as main transcript	c.*429C>T		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.*429C>T	3_prime_UTR_variant	4/4	1	NM_006087.4	P1
	ENST00000599292.1 linkuse as main transcript	n.226G>A	non_coding_transcript_exon_variant	2/2	3
	ENST00000596027.1 linkuse as main transcript	n.231-1G>A	splice_acceptor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

151942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00431

GnomAD4 exome

AF:

0.000428

AC:

AN:

70012

Hom.:

Cov.:

AF XY:

0.000220

AC XY:

AN XY:

36394

show subpopulations

Gnomad4 AFR exome

AF:

0.00876

Gnomad4 AMR exome

AF:

0.00194

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:

0.00

Gnomad4 OTH exome

AF:

0.000273

GnomAD4 genome

AF:

0.00352

AC:

536

AN:

152060

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0119

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00270

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Torsion dystonia 4

Benign:1

Benign, 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 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. -

Hypomyelinating leukodystrophy 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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