19-6494764-C-T

Variant names:

• chr19-6494764-C-T
• rs8113500
• NM_006087.4:c.*400G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006087.4(TUBB4A):​c.*400G>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 0.0211 in 259,484 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (276 hom., cov: 30)
  • Exomes 𝑓: 0.0046 (34 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.239
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-6494764-C-T is Benign according to our data. Variant chr19-6494764-C-T is described in ClinVar as Benign. ClinVar VariationId is 330254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

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.*400G>A		3_prime_UTR	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.*400G>A		3_prime_UTR	Exon 5 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.*400G>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.*400G>A		3_prime_UTR	Exon 4 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000714086.1		c.*1274G>A		3_prime_UTR	Exon 4 of 4	ENSP00000519377.1	A0AAQ5BHG7
	ENSG00000268191	ENST00000596027.1	TSL:5	n.259C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 4973 AN: 151378 Hom.: 278 Cov.: 30

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0212

GnomAD4 exome AF: 0.00458 AC: 495 AN: 107988 Hom.: 34 Cov.: 0 AF XY: 0.00406 AC XY: 230 AN XY: 56584

African (AFR) AF: 0.108 AC: 421 AN: 3884

American (AMR) AF: 0.00519 AC: 26 AN: 5010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2704

East Asian (EAS) AF: 0.00 AC: 0 AN: 5722

South Asian (SAS) AF: 0.000217 AC: 3 AN: 13820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4134

Middle Eastern (MID) AF: 0.00254 AC: 1 AN: 394

European-Non Finnish (NFE) AF: 0.000240 AC: 16 AN: 66654

Other (OTH) AF: 0.00494 AC: 28 AN: 5666

GnomAD4 genome AF: 0.0329 AC: 4978 AN: 151496 Hom.: 276 Cov.: 30 AF XY: 0.0319 AC XY: 2360 AN XY: 73968

African (AFR) AF: 0.115 AC: 4722 AN: 41192

American (AMR) AF: 0.0127 AC: 192 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10470

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67950

Other (OTH) AF: 0.0210 AC: 44 AN: 2100

Alfa AF: 0.0117 Hom.: 64

Bravo AF: 0.0374

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.88
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs8113500; hg19: chr19-6494775;