rs118102196

chr19-6495578-G-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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.938

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=-0.57).
• 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. This position pass quality control queck.
• BS2: High AC in GnomAd at 2276 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4A	NM_006087.4	c.921C>T	p.His307=	synonymous_variant	4/4	ENST00000264071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4A	ENST00000264071.7	c.921C>T	p.His307=	synonymous_variant	4/4	1	NM_006087.4	P1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2276 AN: 152220 Hom.: 24 Cov.: 32

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.: 44 AF XY: 0.0167 AC XY: 2266 AN XY: 135374

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.: 32 AF XY: 0.0207 AC XY: 15069 AN XY: 727140

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.: 24 Cov.: 32 AF XY: 0.0134 AC XY: 998 AN XY: 74496

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.: 13

Bravo AF: 0.0150

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0256

EpiControl AF: 0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 6 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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. -

TUBB4A-related disorder Benign:1

Benign, criteria provided, single submitter

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

Other links and lift over

dbSNP: rs118102196; hg19: chr19-6495589;