rs144969662

Positions:

• chr19-6495593-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006087.4(TUBB4A):​c.906G>A​(p.Ala302=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,613,984 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (9 hom.)
• Consequence: TUBB4A NM_006087.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.460

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-6495593-C-T is Benign according to our data. Variant chr19-6495593-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 330262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6495593-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00322 (491/152354) while in subpopulation NFE AF= 0.00419 (285/68018). AF 95% confidence interval is 0.00379. There are 2 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 491 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.906G>A	p.Ala302=	synonymous_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.906G>A	p.Ala302=	synonymous_variant	4/4	1	NM_006087.4	ENSP00000264071	P1

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 491 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00378 AC: 945 AN: 250158 Hom.: 2 AF XY: 0.00369 AC XY: 499 AN XY: 135344

Gnomad AFR exome AF: 0.000624

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00568

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.00420

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00349 AC: 5108 AN: 1461630 Hom.: 9 Cov.: 32 AF XY: 0.00351 AC XY: 2551 AN XY: 727150

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00724

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00297

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.00343

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00322 AC: 491 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74504

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00989

Gnomad4 NFE AF: 0.00419

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00416 Hom.: 1

Bravo AF: 0.00228

EpiCase AF: 0.00360

EpiControl AF: 0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2020	- -

Hypomyelinating leukodystrophy 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TUBB4A: BP4, BP7 -
Likely 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

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Torsion dystonia 4;C2676244:Hypomyelinating leukodystrophy 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2022

- -

TUBB4A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.6
DANN	Benign	0.76

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: rs144969662; hg19: chr19-6495604;