19-6494904-C-G

Position:

• chr19-6494904-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.*260G>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 0.571 in 570,170 control chromosomes in the GnomAD database, including 95,935 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21460 hom., cov: 29)
  • Exomes 𝑓: 0.59 (74475 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.726

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=-0.88).
• BP6: Variant 19-6494904-C-G is Benign according to our data. Variant chr19-6494904-C-G is described in ClinVar as [Benign]. Clinvar id is 330255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.*260G>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.*260G>C		3_prime_UTR_variant	4/4	1	NM_006087.4	P1
	ENST00000596027.1	n.399C>G		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78261 AN: 151580 Hom.: 21461 Cov.: 29

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.587

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.547

GnomAD4 exome AF: 0.590 AC: 247072 AN: 418472 Hom.: 74475 Cov.: 3 AF XY: 0.594 AC XY: 130209 AN XY: 219028

Gnomad4 AFR exome AF: 0.312

Gnomad4 AMR exome AF: 0.611

Gnomad4 ASJ exome AF: 0.580

Gnomad4 EAS exome AF: 0.751

Gnomad4 SAS exome AF: 0.635

Gnomad4 FIN exome AF: 0.604

Gnomad4 NFE exome AF: 0.578

Gnomad4 OTH exome AF: 0.566

GnomAD4 genome AF: 0.516 AC: 78278 AN: 151698 Hom.: 21460 Cov.: 29 AF XY: 0.524 AC XY: 38791 AN XY: 74092

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.588

Gnomad4 ASJ AF: 0.581

Gnomad4 EAS AF: 0.717

Gnomad4 SAS AF: 0.656

Gnomad4 FIN AF: 0.634

Gnomad4 NFE AF: 0.577

Gnomad4 OTH AF: 0.545

Alfa AF: 0.552 Hom.: 2976

Bravo AF: 0.501

Asia WGS AF: 0.653 AC: 2273 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 19, 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	-0.88
CADD	Benign	0.82
DANN	Benign	0.68
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: rs3099129; hg19: chr19-6494915;