19-6494464-A-T

Position:

• chr19-6494464-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000264071.7(TUBB4A):​c.*700T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 147,780 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (153 hom., cov: 30)
  • Exomes 𝑓: 0.0078 (0 hom.)
• Consequence: TUBB4A ENST00000264071.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.810

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-6494464-A-T is Benign according to our data. Variant chr19-6494464-A-T is described in ClinVar as [Benign]. Clinvar id is 330249.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.*700T>A		3_prime_UTR_variant	4/4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7	c.*700T>A		3_prime_UTR_variant	4/4	1	NM_006087.4	ENSP00000264071	P1
	ENST00000596027.1	n.145A>T		non_coding_transcript_exon_variant	1/2	5
	ENST00000599292.1	n.145A>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4804 AN: 146252 Hom.: 154 Cov.: 30

Gnomad AFR AF: 0.0883

Gnomad AMI AF: 0.00227

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00235

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000441

Gnomad FIN AF: 0.0257

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0179

GnomAD4 exome AF: 0.00782 AC: 11 AN: 1406 Hom.: 0 Cov.: 0 AF XY: 0.00532 AC XY: 4 AN XY: 752

Gnomad4 AFR exome AF: 0.0833

Gnomad4 AMR exome AF: 0.0176

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.00387

Gnomad4 OTH exome AF: 0.0333

GnomAD4 genome AF: 0.0329 AC: 4809 AN: 146374 Hom.: 153 Cov.: 30 AF XY: 0.0330 AC XY: 2353 AN XY: 71232

Gnomad4 AFR AF: 0.0882

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.00235

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000441

Gnomad4 FIN AF: 0.0257

Gnomad4 NFE AF: 0.0115

Gnomad4 OTH AF: 0.0177

Alfa AF: 0.00910 Hom.: 3

Bravo AF: 0.0332

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Torsion dystonia 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Hypomyelinating leukodystrophy 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.4
DANN	Benign	0.77
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

Other links and lift over

dbSNP: rs73920690; hg19: chr19-6494475;