chr19-6494904-C-G

Variant names:

• chr19-6494904-C-G
• rs3099129
• NM_006087.4:c.*260G>C

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.*260G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 570,170 control chromosomes in the GnomAD database, including 95,935 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21460 hom., cov: 29)
  • Exomes 𝑓: 0.59 (74475 hom.)
• Consequence: TUBB4A NM_006087.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.726
• Publications: 7 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=-0.88).
• BP6: Variant 19-6494904-C-G is Benign according to our data. Variant chr19-6494904-C-G is described in ClinVar as Benign. ClinVar VariationId is 330255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.698 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.*260G>C		3_prime_UTR	Exon 4 of 4	NP_006078.2
	TUBB4A	NM_001289123.2		c.*260G>C		3_prime_UTR	Exon 5 of 5	NP_001276052.1	M0QZL7
	TUBB4A	NM_001289127.2		c.*260G>C		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.*260G>C		3_prime_UTR	Exon 4 of 4	ENSP00000264071.1	P04350
	TUBB4A	ENST00000714086.1		c.*1134G>C		3_prime_UTR	Exon 4 of 4	ENSP00000519377.1	A0AAQ5BHG7
	ENSG00000268191	ENST00000596027.1	TSL:5	n.399C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78261 AN: 151580 Hom.: 21461 Cov.: 29

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.587

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.547

GnomAD4 exome AF: 0.590 AC: 247072 AN: 418472 Hom.: 74475 Cov.: 3 AF XY: 0.594 AC XY: 130209 AN XY: 219028

African (AFR) AF: 0.312 AC: 3767 AN: 12058

American (AMR) AF: 0.611 AC: 10692 AN: 17496

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 7531 AN: 12980

East Asian (EAS) AF: 0.751 AC: 21715 AN: 28898

South Asian (SAS) AF: 0.635 AC: 26164 AN: 41230

European-Finnish (FIN) AF: 0.604 AC: 16222 AN: 26878

Middle Eastern (MID) AF: 0.563 AC: 1033 AN: 1834

European-Non Finnish (NFE) AF: 0.578 AC: 146052 AN: 252554

Other (OTH) AF: 0.566 AC: 13896 AN: 24544

GnomAD4 genome AF: 0.516 AC: 78278 AN: 151698 Hom.: 21460 Cov.: 29 AF XY: 0.524 AC XY: 38791 AN XY: 74092

African (AFR) AF: 0.312 AC: 12878 AN: 41334

American (AMR) AF: 0.588 AC: 8943 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 2013 AN: 3466

East Asian (EAS) AF: 0.717 AC: 3693 AN: 5150

South Asian (SAS) AF: 0.656 AC: 3148 AN: 4802

European-Finnish (FIN) AF: 0.634 AC: 6672 AN: 10522

Middle Eastern (MID) AF: 0.586 AC: 170 AN: 290

European-Non Finnish (NFE) AF: 0.577 AC: 39202 AN: 67908

Other (OTH) AF: 0.545 AC: 1148 AN: 2106

Alfa AF: 0.552 Hom.: 2976

Bravo AF: 0.501

Asia WGS AF: 0.653 AC: 2273 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	-0.88
CADD	Benign	0.82
DANN	Benign	0.68
PhyloP100		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3099129; hg19: chr19-6494915;