19-6495111-C-T

Variant names:

• chr19-6495111-C-T
• rs113953942
• NM_006087.4:c.*53G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006087.4(TUBB4A):​c.*53G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,594,184 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (37 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.275
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ENSG00000268191 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-6495111-C-T is Benign according to our data. Variant chr19-6495111-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 330259.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2020/152048) while in subpopulation AFR AF = 0.0463 (1919/41452). AF 95% confidence interval is 0.0446. There are 44 homozygotes in GnomAd4. There are 929 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2020 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.*53G>A		3_prime_UTR	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.*53G>A		3_prime_UTR	Exon 5 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.*53G>A		3_prime_UTR	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.*53G>A		3_prime_UTR	Exon 4 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000714086.1		c.*927G>A		3_prime_UTR	Exon 4 of 4	ENSP00000519377.1	A0AAQ5BHG7
	TUBB4A	ENST00000598635.2	TSL:4	c.*53G>A		downstream_gene	N/A	ENSP00000470627.2	M0QZL7

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2016 AN: 151932 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00959

GnomAD4 exome AF: 0.00129 AC: 1857 AN: 1442136 Hom.: 37 Cov.: 31 AF XY: 0.00108 AC XY: 774 AN XY: 715616

African (AFR) AF: 0.0471 AC: 1557 AN: 33088

American (AMR) AF: 0.00190 AC: 83 AN: 43724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24950

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39468

South Asian (SAS) AF: 0.0000836 AC: 7 AN: 83692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52734

Middle Eastern (MID) AF: 0.000397 AC: 2 AN: 5040

European-Non Finnish (NFE) AF: 0.0000691 AC: 76 AN: 1099898

Other (OTH) AF: 0.00218 AC: 130 AN: 59542

GnomAD4 genome AF: 0.0133 AC: 2020 AN: 152048 Hom.: 44 Cov.: 32 AF XY: 0.0125 AC XY: 929 AN XY: 74332

African (AFR) AF: 0.0463 AC: 1919 AN: 41452

American (AMR) AF: 0.00458 AC: 70 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67980

Other (OTH) AF: 0.00949 AC: 20 AN: 2108

Alfa AF: 0.00387 Hom.: 1

Bravo AF: 0.0154

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hypomyelinating leukodystrophy 6 (1)
-	-	1	Torsion dystonia 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.48
PhyloP100		-0.28
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: rs113953942; hg19: chr19-6495122;