chr19-6495068-G-C

Variant names:

• chr19-6495068-G-C
• rs449824
• NM_006087.4:c.*96C>G

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.*96C>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 0.0538 in 1,453,870 control chromosomes in the GnomAD database, including 3,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (411 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2708 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0210
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-6495068-G-C is Benign according to our data. Variant chr19-6495068-G-C is described in ClinVar as Benign. ClinVar VariationId is 330258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.202 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.*96C>G		3_prime_UTR	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.*96C>G		3_prime_UTR	Exon 5 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.*96C>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.*96C>G		3_prime_UTR	Exon 4 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000714086.1		c.*970C>G		3_prime_UTR	Exon 4 of 4	ENSP00000519377.1	A0AAQ5BHG7
	TUBB4A	ENST00000598635.2	TSL:4	c.*96C>G		downstream_gene	N/A	ENSP00000470627.2	M0QZL7

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9784 AN: 151712 Hom.: 411 Cov.: 32

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0503

Gnomad ASJ AF: 0.0875

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0614

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0454

Gnomad OTH AF: 0.0754

GnomAD4 exome AF: 0.0525 AC: 68407 AN: 1302040 Hom.: 2708 Cov.: 21 AF XY: 0.0548 AC XY: 35300 AN XY: 644350

African (AFR) AF: 0.0779 AC: 2322 AN: 29804

American (AMR) AF: 0.0564 AC: 1951 AN: 34568

Ashkenazi Jewish (ASJ) AF: 0.0852 AC: 1830 AN: 21470

East Asian (EAS) AF: 0.201 AC: 7459 AN: 37126

South Asian (SAS) AF: 0.114 AC: 8365 AN: 73282

European-Finnish (FIN) AF: 0.0612 AC: 3024 AN: 49394

Middle Eastern (MID) AF: 0.0839 AC: 333 AN: 3968

European-Non Finnish (NFE) AF: 0.0400 AC: 39871 AN: 997962

Other (OTH) AF: 0.0597 AC: 3252 AN: 54466

GnomAD4 genome AF: 0.0644 AC: 9777 AN: 151830 Hom.: 411 Cov.: 32 AF XY: 0.0664 AC XY: 4925 AN XY: 74194

African (AFR) AF: 0.0748 AC: 3098 AN: 41394

American (AMR) AF: 0.0504 AC: 767 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.0875 AC: 303 AN: 3462

East Asian (EAS) AF: 0.212 AC: 1086 AN: 5114

South Asian (SAS) AF: 0.113 AC: 541 AN: 4790

European-Finnish (FIN) AF: 0.0614 AC: 650 AN: 10584

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0454 AC: 3085 AN: 67948

Other (OTH) AF: 0.0756 AC: 159 AN: 2104

Alfa AF: 0.0573 Hom.: 40

Bravo AF: 0.0634

Asia WGS AF: 0.130 AC: 450 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.87
CADD	Benign	1.1
DANN	Benign	0.72
PhyloP100		-0.021
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: rs449824; hg19: chr19-6495079; COSMIC: COSV107249154; COSMIC: COSV107249154;