19-6495068-G-C

Variant names:

• chr19-6495068-G-C
• rs449824
• NM_006087.4:c.*96C>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.*96C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0538 in 1,453,870 control chromosomes in the GnomAD database, including 3,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (411 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2708 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0210

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]

ENSG00000268191 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-6495068-G-C is Benign according to our data. Variant chr19-6495068-G-C is described in ClinVar as [Benign]. Clinvar id is 330258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.*96C>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071	c.*96C>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_006087.4	ENSP00000264071.1
ENSG00000268191	ENST00000596027.1	n.*43G>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9784 AN: 151712 Hom.: 411 Cov.: 32

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.0875

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0614

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0754

GnomAD4 exome AF: 0.0525 AC: 68407 AN: 1302040 Hom.: 2708 Cov.: 21 AF XY: 0.0548 AC XY: 35300 AN XY: 644350

Gnomad4 AFR exome AF: 0.0779

Gnomad4 AMR exome AF: 0.0564

Gnomad4 ASJ exome AF: 0.0852

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0612

Gnomad4 NFE exome AF: 0.0400

Gnomad4 OTH exome AF: 0.0597

GnomAD4 genome AF: 0.0644 AC: 9777 AN: 151830 Hom.: 411 Cov.: 32 AF XY: 0.0664 AC XY: 4925 AN XY: 74194

Gnomad4 AFR AF: 0.0748

Gnomad4 AMR AF: 0.0504

Gnomad4 ASJ AF: 0.0875

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.0614

Gnomad4 NFE AF: 0.0454

Gnomad4 OTH AF: 0.0756

Alfa AF: 0.0573 Hom.: 40

Bravo AF: 0.0634

Asia WGS AF: 0.130 AC: 450 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Torsion dystonia 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.87
CADD	Benign	1.1
DANN	Benign	0.72

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: rs449824; hg19: chr19-6495079;