19-6501375-C-T

Variant names:

• chr19-6501375-C-T
• rs150812047
• NM_006087.4:c.189G>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.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 (★★). Synonymous variant affecting the same amino acid position (i.e. A63A) has been classified 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
• Publications: 6 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 (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 Benign/Likely_benign. ClinVar VariationId is 330267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 378 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.189G>A	p.Ala63Ala	synonymous	Exon 3 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.342G>A	p.Ala114Ala	synonymous	Exon 4 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.324G>A	p.Ala108Ala	synonymous	Exon 4 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.189G>A	p.Ala63Ala	synonymous	Exon 3 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000714086.1		c.214G>A	p.Gly72Ser	missense	Exon 3 of 4	ENSP00000519377.1	A0AAQ5BHG7
	TUBB4A	ENST00000598006.1	TSL:2	c.146G>A	p.Arg49Gln	missense	Exon 3 of 4	ENSP00000472795.1	M0R2T4

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

GnomAD2 exomes AF: 0.00215 AC: 540 AN: 250720 AF XY: 0.00224

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 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

African (AFR) AF: 0.000418 AC: 14 AN: 33472

American (AMR) AF: 0.00181 AC: 81 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86242

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53390

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00391 AC: 4346 AN: 1111802

Other (OTH) AF: 0.00245 AC: 148 AN: 60370

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

African (AFR) AF: 0.000794 AC: 33 AN: 41576

American (AMR) AF: 0.00137 AC: 21 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00447 AC: 304 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00323 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hypomyelinating leukodystrophy 6 (2)
-	-	1	Torsion dystonia 4 (1)
-	-	1	TUBB4A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
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
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0048	T
PhyloP100		-0.56
Sift4G	Benign	0.40	T
Vest4		0.22
MVP		0.42
GERP RS		-7.7
PromoterAI		0.0039	Neutral
Mutation Taster		=90/10	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: rs150812047; hg19: chr19-6501386; COSMIC: COSV108759749;