19-6495053-C-G

Position:

• chr19-6495053-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006087.4(TUBB4A):​c.*111G>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 0.754 in 1,308,468 control chromosomes in the GnomAD database, including 372,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44103 hom., cov: 27)
  • Exomes 𝑓: 0.75 (328652 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.50

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-6495053-C-G is Benign according to our data. Variant chr19-6495053-C-G is described in ClinVar as [Benign]. Clinvar id is 330256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.*111G>C		3_prime_UTR_variant	4/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7	c.*111G>C		3_prime_UTR_variant	4/4	1	NM_006087.4	P1
	ENST00000596027.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115154 AN: 151090 Hom.: 44070 Cov.: 27

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.838

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.767

GnomAD4 exome AF: 0.753 AC: 871148 AN: 1157258 Hom.: 328652 Cov.: 16 AF XY: 0.751 AC XY: 431983 AN XY: 575204

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.854

Gnomad4 ASJ exome AF: 0.736

Gnomad4 EAS exome AF: 0.752

Gnomad4 SAS exome AF: 0.715

Gnomad4 FIN exome AF: 0.810

Gnomad4 NFE exome AF: 0.750

Gnomad4 OTH exome AF: 0.748

GnomAD4 genome AF: 0.762 AC: 115244 AN: 151210 Hom.: 44103 Cov.: 27 AF XY: 0.763 AC XY: 56367 AN XY: 73832

Gnomad4 AFR AF: 0.757

Gnomad4 AMR AF: 0.810

Gnomad4 ASJ AF: 0.728

Gnomad4 EAS AF: 0.712

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.838

Gnomad4 NFE AF: 0.754

Gnomad4 OTH AF: 0.770

Alfa AF: 0.685 Hom.: 1574

Bravo AF: 0.759

Asia WGS AF: 0.745 AC: 2593 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.92
CADD	Benign	0.26
DANN	Benign	0.45

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: rs446199; hg19: chr19-6495064;