19-6495593-C-T

Variant names:

• chr19-6495593-C-T
• rs144969662
• NM_006087.4:c.906G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006087.4(TUBB4A):​c.906G>A​(p.Ala302Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,613,984 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A302A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (9 hom.)
• Consequence: TUBB4A NM_006087.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.460
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), Illumina
• TUBB4A-related neurologic disorder

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
• torsion dystonia 4

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-6495593-C-T is Benign according to our data. Variant chr19-6495593-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 330262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00322 (491/152354) while in subpopulation NFE AF = 0.00419 (285/68018). AF 95% confidence interval is 0.00379. There are 2 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 491 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006087.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	NM_006087.4	MANE Select	c.906G>A	p.Ala302Ala	synonymous	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.1059G>A	p.Ala353Ala	synonymous	Exon 5 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.1041G>A	p.Ala347Ala	synonymous	Exon 5 of 5	NP_001276056.1	M0R278

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4A	ENST00000264071.7	TSL:1 MANE Select	c.906G>A	p.Ala302Ala	synonymous	Exon 4 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000598635.2	TSL:4	c.1059G>A	p.Ala353Ala	synonymous	Exon 5 of 5	ENSP00000470627.2	M0QZL7
	TUBB4A	ENST00000597686.6	TSL:4	c.1041G>A	p.Ala347Ala	synonymous	Exon 5 of 5	ENSP00000472375.2	M0R278

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 491 AN: 152236 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00378 AC: 945 AN: 250158 AF XY: 0.00369

Gnomad AFR exome AF: 0.000624

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00568

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.00420

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00349 AC: 5108 AN: 1461630 Hom.: 9 Cov.: 32 AF XY: 0.00351 AC XY: 2551 AN XY: 727150

African (AFR) AF: 0.000478 AC: 16 AN: 33476

American (AMR) AF: 0.00103 AC: 46 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00724 AC: 189 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00297 AC: 256 AN: 86240

European-Finnish (FIN) AF: 0.0111 AC: 593 AN: 53370

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5758

European-Non Finnish (NFE) AF: 0.00343 AC: 3811 AN: 1111892

Other (OTH) AF: 0.00305 AC: 184 AN: 60384

GnomAD4 genome AF: 0.00322 AC: 491 AN: 152354 Hom.: 2 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74504

African (AFR) AF: 0.000673 AC: 28 AN: 41594

American (AMR) AF: 0.00229 AC: 35 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.00989 AC: 105 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 68018

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00416 Hom.: 1

Bravo AF: 0.00228

EpiCase AF: 0.00360

EpiControl AF: 0.00415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hypomyelinating leukodystrophy 6 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Torsion dystonia 4 (1)
-	-	1	Torsion dystonia 4;C2676244:Hypomyelinating leukodystrophy 6 (1)
-	-	1	TUBB4A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.6
DANN	Benign	0.76
PhyloP100		0.46
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs144969662; hg19: chr19-6495604;