NM_006087.4:c.189G>A

Variant names:

• chr19-6501375-C-T
• rs150812047
• NM_006087.4:c.189G>A

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.189G>A​(p.Ala63Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 1,613,854 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 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (11 hom.)
• Consequence: TUBB4A NM_006087.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.557

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 (MetaRNN=0.004796207).
• BP6: Variant 19-6501375-C-T is Benign according to our data. Variant chr19-6501375-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 330267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-6501375-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.557 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00248 (378/152314) while in subpopulation NFE AF= 0.00447 (304/68016). AF 95% confidence interval is 0.00406. There are 0 homozygotes in gnomad4. There are 188 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.189G>A	p.Ala63Ala	synonymous_variant	Exon 3 of 4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7	c.189G>A	p.Ala63Ala	synonymous_variant	Exon 3 of 4	1	NM_006087.4	ENSP00000264071.1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00215 AC: 540 AN: 250720 Hom.: 0 AF XY: 0.00224 AC XY: 303 AN XY: 135500

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.000995

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00326 AC: 4763 AN: 1461540 Hom.: 11 Cov.: 31 AF XY: 0.00329 AC XY: 2390 AN XY: 727032

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000919

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00391

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00252 AC XY: 188 AN XY: 74480

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00369 Hom.: 0

Bravo AF: 0.00221

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26318963) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TUBB4A: PP2, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hypomyelinating leukodystrophy 6 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Torsion dystonia 4 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

TUBB4A-related disorder Benign:1

May 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.2
DANN	Benign	0.93
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.36	T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0048	T;T
Sift4G	Benign	0.40	T;T
Vest4		0.22
MVP		0.42
GERP RS		-7.7

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: rs150812047; hg19: chr19-6501386;