NM_006087.4:c.*69C>G

Variant names:

• chr19-6495095-G-C
• rs564748070
• NM_006087.4:c.*69C>G

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.*69C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,573,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.920
• 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

ENSG00000268191 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-6495095-G-C is Benign according to our data. Variant chr19-6495095-G-C is described in ClinVar as Benign. ClinVar VariationId is 894183.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000749 (114/152148) while in subpopulation AFR AF = 0.00265 (110/41520). AF 95% confidence interval is 0.00225. There are 1 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 114 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.*69C>G		3_prime_UTR	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.*69C>G		3_prime_UTR	Exon 5 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.*69C>G		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.*69C>G		3_prime_UTR	Exon 4 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000714086.1		c.*943C>G		3_prime_UTR	Exon 4 of 4	ENSP00000519377.1	A0AAQ5BHG7
	TUBB4A	ENST00000598635.2	TSL:4	c.*69C>G		downstream_gene	N/A	ENSP00000470627.2	M0QZL7

Frequencies

GnomAD3 genomes AF: 0.000750 AC: 114 AN: 152030 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.0000654 AC: 93 AN: 1421498 Hom.: 0 Cov.: 29 AF XY: 0.0000625 AC XY: 44 AN XY: 704406

African (AFR) AF: 0.00264 AC: 86 AN: 32622

American (AMR) AF: 0.0000236 AC: 1 AN: 42404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39220

South Asian (SAS) AF: 0.00 AC: 0 AN: 81206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4710

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1086366

Other (OTH) AF: 0.0000851 AC: 5 AN: 58764

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74386

African (AFR) AF: 0.00265 AC: 110 AN: 41520

American (AMR) AF: 0.000197 AC: 3 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000638

ClinVar

ClinVar submissions

Significance: 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	-0.87
CADD	Benign	2.5
DANN	Benign	0.77
PhyloP100		0.92

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: rs564748070; hg19: chr19-6495106;