rs118102196

Positions:

chr19-6495578-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006087.4(TUBB4A):c.921C>T(p.His307=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 1,613,948 control chromosomes in the GnomAD database, including 429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 32)

Exomes 𝑓: 0.021 ( 405 hom. )

Consequence

TUBB4A
NM_006087.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.938

Variant links:

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]

TUBB4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 19-6495578-G-A is Benign according to our data. Variant chr19-6495578-G-A is described in ClinVar as [Benign]. Clinvar id is 240288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6495578-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.938 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0149 (2272/152338) while in subpopulation NFE AF= 0.0239 (1623/68020). AF 95% confidence interval is 0.0229. There are 24 homozygotes in gnomad4. There are 998 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2272 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4 linkuse as main transcript	c.921C>T	p.His307=	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 linkuse as main transcript	c.921C>T	p.His307=	synonymous_variant	4/4	1	NM_006087.4	ENSP00000264071	P1

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2276

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00429

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00620

Gnomad FIN

AF:

0.00659

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0239

Gnomad OTH

AF:

0.0211

GnomAD3 exomes

AF:

0.0164

AC:

4102

AN:

250082

Hom.:

AF XY:

0.0167

AC XY:

2266

AN XY:

135374

show subpopulations

Gnomad AFR exome

AF:

0.00331

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0289

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00844

Gnomad FIN exome

AF:

0.00634

Gnomad NFE exome

AF:

0.0250

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0211

AC:

30774

AN:

1461610

Hom.:

405

Cov.:

AF XY:

0.0207

AC XY:

15069

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00353

Gnomad4 AMR exome

AF:

0.0119

Gnomad4 ASJ exome

AF:

0.0288

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00864

Gnomad4 FIN exome

AF:

0.00828

Gnomad4 NFE exome

AF:

0.0240

Gnomad4 OTH exome

AF:

0.0206

GnomAD4 genome

AF:

0.0149

AC:

2272

AN:

152338

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

998

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00428

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.0305

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00600

Gnomad4 FIN

AF:

0.00659

Gnomad4 NFE

AF:

0.0239

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0219

Hom.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0256

EpiControl

AF:

0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2016

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. -

Torsion dystonia 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

TUBB4A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 30, 2020

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

-0.57

CADD

Benign

9.4

DANN

Benign

0.60

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over