rs143804865

Variant names:

• chr6-30722324-T-A
• rs143804865
• NM_178014.4:c.58-213T>A

Variant summary

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

The NM_178014.4(TUBB):​c.58-213T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 552,606 control chromosomes in the GnomAD database, including 787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (241 hom., cov: 32)
  • Exomes 𝑓: 0.019 (546 hom.)
• Consequence: TUBB NM_178014.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.166
• Publications: 1 publications found

Genes affected

TUBB (HGNC:20778): (tubulin beta class I) This gene encodes a beta tubulin protein. This protein forms a dimer with alpha tubulin and acts as a structural component of microtubules. Mutations in this gene cause cortical dysplasia, complex, with other brain malformations 6. Alternative splicing results in multiple splice variants. There are multiple pseudogenes for this gene on chromosomes 1, 6, 7, 8, 9, and 13. [provided by RefSeq, Jun 2014]

TUBB Gene-Disease associations (from GenCC):

• complex cortical dysplasia with other brain malformations 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• multiple benign circumferential skin creases on limbs 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• TUBB3-related tubulinopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina
• multiple benign circumferential skin creases on limbs

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-30722324-T-A is Benign according to our data. Variant chr6-30722324-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1181982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178014.4. 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
	TUBB	NM_178014.4	MANE Select	c.58-213T>A		intron	N/A	NP_821133.1	Q5SU16
	TUBB	NM_001293212.2		c.118-213T>A		intron	N/A	NP_001280141.1
	TUBB	NM_001293214.2		c.35-594T>A		intron	N/A	NP_001280143.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB	ENST00000327892.13	TSL:1 MANE Select	c.58-213T>A		intron	N/A	ENSP00000339001.7	P07437
	TUBB	ENST00000396389.5	TSL:5	c.3+62T>A		intron	N/A	ENSP00000379672.1	Q5JP53
	TUBB	ENST00000940307.1		c.58-213T>A		intron	N/A	ENSP00000610366.1

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 3001 AN: 152056 Hom.: 236 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0187

GnomAD4 exome AF: 0.0188 AC: 7519 AN: 400432 Hom.: 546 Cov.: 3 AF XY: 0.0170 AC XY: 3594 AN XY: 211390

African (AFR) AF: 0.00239 AC: 27 AN: 11312

American (AMR) AF: 0.144 AC: 2429 AN: 16908

Ashkenazi Jewish (ASJ) AF: 0.00147 AC: 18 AN: 12260

East Asian (EAS) AF: 0.158 AC: 4300 AN: 27240

South Asian (SAS) AF: 0.00781 AC: 332 AN: 42504

European-Finnish (FIN) AF: 0.0000382 AC: 1 AN: 26184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1776

European-Non Finnish (NFE) AF: 0.000297 AC: 71 AN: 239166

Other (OTH) AF: 0.0148 AC: 341 AN: 23082

GnomAD4 genome AF: 0.0198 AC: 3008 AN: 152174 Hom.: 241 Cov.: 32 AF XY: 0.0225 AC XY: 1676 AN XY: 74428

African (AFR) AF: 0.00193 AC: 80 AN: 41524

American (AMR) AF: 0.128 AC: 1953 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.171 AC: 882 AN: 5170

South Asian (SAS) AF: 0.00663 AC: 32 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68004

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0107 Hom.: 12

Bravo AF: 0.0293

Asia WGS AF: 0.0400 AC: 139 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.5
DANN	Benign	0.87
PhyloP100		0.17
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: rs143804865; hg19: chr6-30690101;