rs149903666

Variant names:

• chr19-6495584-C-T
• rs149903666
• NM_006087.4:c.915G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006087.4(TUBB4A):​c.915G>A​(p.Pro305Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,613,872 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (13 hom.)
• Consequence: TUBB4A NM_006087.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.18
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 19-6495584-C-T is Benign according to our data. Variant chr19-6495584-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212502.
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00259 (394/152320) while in subpopulation NFE AF = 0.00223 (152/68014). AF 95% confidence interval is 0.00195. There are 2 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 394 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.915G>A	p.Pro305Pro	synonymous	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.1068G>A	p.Pro356Pro	synonymous	Exon 5 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.1050G>A	p.Pro350Pro	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.915G>A	p.Pro305Pro	synonymous	Exon 4 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000598635.2	TSL:4	c.1068G>A	p.Pro356Pro	synonymous	Exon 5 of 5	ENSP00000470627.2	M0QZL7
	TUBB4A	ENST00000597686.6	TSL:4	c.1050G>A	p.Pro350Pro	synonymous	Exon 5 of 5	ENSP00000472375.2	M0R278

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0206

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00292 AC: 730 AN: 249720 AF XY: 0.00289

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.00192

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00198 AC: 2901 AN: 1461552 Hom.: 13 Cov.: 32 AF XY: 0.00194 AC XY: 1411 AN XY: 727088

African (AFR) AF: 0.000269 AC: 9 AN: 33474

American (AMR) AF: 0.000582 AC: 26 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86236

European-Finnish (FIN) AF: 0.0191 AC: 1020 AN: 53348

Middle Eastern (MID) AF: 0.000524 AC: 3 AN: 5728

European-Non Finnish (NFE) AF: 0.00156 AC: 1737 AN: 1111882

Other (OTH) AF: 0.00146 AC: 88 AN: 60378

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.00332 AC XY: 247 AN XY: 74486

African (AFR) AF: 0.000289 AC: 12 AN: 41574

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0206 AC: 219 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00223 AC: 152 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00195 Hom.: 1

Bravo AF: 0.000979

EpiCase AF: 0.00104

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Hypomyelinating leukodystrophy 6 (2)
-	-	2	not provided (2)
-	1	1	not specified (2)
-	-	1	Torsion dystonia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.5
DANN	Benign	0.83
PhyloP100		-1.2
Mutation Taster		=100/0	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: rs149903666; hg19: chr19-6495595;