19-6495212-C-T

Position:

chr19-6495212-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_006087.4(TUBB4A):c.1287G>A(p.Thr429Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0219 in 1,613,922 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 31 hom., cov: 32)

Exomes 𝑓: 0.022 ( 406 hom. )

Consequence

TUBB4A
NM_006087.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -5.13

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 19-6495212-C-T is Benign according to our data. Variant chr19-6495212-C-T is described in ClinVar as [Benign]. Clinvar id is 330260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6495212-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-5.13 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.017 (2584/152240) while in subpopulation NFE AF= 0.0251 (1706/67986). AF 95% confidence interval is 0.0241. There are 31 homozygotes in gnomad4. There are 1221 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2584 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBB4A	NM_006087.4 link	c.1287G>A	p.Thr429Thr	synonymous_variant	4/4	ENST00000264071.7	NP_006078.2	P04350

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7 link	c.1287G>A	p.Thr429Thr	synonymous_variant	4/4	1	NM_006087.4	ENSP00000264071.1		P04350

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2584

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00463

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0295

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0251

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.0179

AC:

4500

AN:

251232

Hom.:

AF XY:

0.0175

AC XY:

2383

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0147

Gnomad ASJ exome

AF:

0.00843

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00356

Gnomad FIN exome

AF:

0.0346

Gnomad NFE exome

AF:

0.0249

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.0224

AC:

32797

AN:

1461682

Hom.:

406

Cov.:

AF XY:

0.0220

AC XY:

15997

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.00400

Gnomad4 AMR exome

AF:

0.0150

Gnomad4 ASJ exome

AF:

0.00918

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00413

Gnomad4 FIN exome

AF:

0.0369

Gnomad4 NFE exome

AF:

0.0253

Gnomad4 OTH exome

AF:

0.0208

GnomAD4 genome

AF:

0.0170

AC:

2584

AN:

152240

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1221

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00465

Gnomad4 AMR

AF:

0.0189

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0295

Gnomad4 NFE

AF:

0.0251

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0180

Hom.:

Bravo

AF:

0.0161

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0225

EpiControl

AF:

0.0238

ClinVar

Significance: Benign

Submissions summary: Benign:5

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 30, 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

Mar 31, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.36

DANN

Benign

0.85

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