19-6494491-T-C

Position:

• chr19-6494491-T-C

Variant summary

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

The ENST00000264071.7(TUBB4A):​c.*673A>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 0.56 in 149,538 control chromosomes in the GnomAD database, including 24,583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24218 hom., cov: 23)
  • Exomes 𝑓: 0.59 (365 hom.)
• Consequence: TUBB4A ENST00000264071.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.837

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=-0.9).
• BP6: Variant 19-6494491-T-C is Benign according to our data. Variant chr19-6494491-T-C is described in ClinVar as [Benign]. Clinvar id is 330250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.*673A>G		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.*673A>G		3_prime_UTR_variant	4/4	1	NM_006087.4	ENSP00000264071	P1
	ENST00000596027.1	n.172T>C		non_coding_transcript_exon_variant	1/2	5
	ENST00000599292.1	n.172T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.560 AC: 82670 AN: 147542 Hom.: 24211 Cov.: 23

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.0958

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.565

GnomAD4 exome AF: 0.585 AC: 1111 AN: 1898 Hom.: 365 Cov.: 0 AF XY: 0.568 AC XY: 563 AN XY: 992

Gnomad4 AFR exome AF: 0.667

Gnomad4 AMR exome AF: 0.560

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.447

Gnomad4 NFE exome AF: 0.641

Gnomad4 OTH exome AF: 0.513

GnomAD4 genome AF: 0.560 AC: 82699 AN: 147640 Hom.: 24218 Cov.: 23 AF XY: 0.551 AC XY: 39516 AN XY: 71780

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.513

Gnomad4 EAS AF: 0.0956

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.596

Gnomad4 NFE AF: 0.650

Gnomad4 OTH AF: 0.558

Alfa AF: 0.628 Hom.: 27256

Bravo AF: 0.556

Asia WGS AF: 0.221 AC: 773 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.81

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: rs1053377; hg19: chr19-6494502;