19-6495212-C-T

Variant names:

• chr19-6495212-C-T
• rs61731566
• NM_006087.4:c.1287G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.13

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]

ENSG00000268191 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
TUBB4A	NM_006087.4	c.1287G>A	p.Thr429Thr	synonymous_variant	Exon 4 of 4	ENST00000264071.7	NP_006078.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4A	ENST00000264071.7	c.1287G>A	p.Thr429Thr	synonymous_variant	Exon 4 of 4	1	NM_006087.4	ENSP00000264071.1
ENSG00000268191	ENST00000596027.1	n.*187C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2584 AN: 152122 Hom.: 31 Cov.: 32

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.: 50 AF XY: 0.0175 AC XY: 2383 AN XY: 135796

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.: 32 AF XY: 0.0220 AC XY: 15997 AN XY: 727150

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.: 31 Cov.: 32 AF XY: 0.0164 AC XY: 1221 AN XY: 74428

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.: 10

Bravo AF: 0.0161

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0225

EpiControl AF: 0.0238

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 31, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Other links and lift over

dbSNP: rs61731566; hg19: chr19-6495223;