chr18-12308317-G-T

Variant names:

• chr18-12308317-G-T
• rs202128106
• NM_032525.3:c.25G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_032525.3(TUBB6):​c.25G>T​(p.Ala9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,482,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A9V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: TUBB6 NM_032525.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40
• Publications: 2 publications found

Genes affected

TUBB6 (HGNC:20776): (tubulin beta 6 class V) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. [provided by Alliance of Genome Resources, Apr 2022]

TUBB6 Gene-Disease associations (from GenCC):

• facial palsy, congenital, with ptosis and velopharyngeal dysfunction

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40769765).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032525.3. 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
	TUBB6	NM_032525.3	MANE Select	c.25G>T	p.Ala9Ser	missense	Exon 1 of 4	NP_115914.1	Q9BUF5
	TUBB6	NM_001303524.1		c.25G>T	p.Ala9Ser	missense	Exon 2 of 5	NP_001290453.1	Q9BUF5
	TUBB6	NM_001303526.2		c.25G>T	p.Ala9Ser	missense	Exon 1 of 3	NP_001290455.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB6	ENST00000317702.10	TSL:1 MANE Select	c.25G>T	p.Ala9Ser	missense	Exon 1 of 4	ENSP00000318697.4	Q9BUF5
	TUBB6	ENST00000591909.5	TSL:1	c.25G>T	p.Ala9Ser	missense	Exon 1 of 4	ENSP00000465040.1	K7EJ64
	TUBB6	ENST00000586810.5	TSL:1	n.25G>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000467348.1	K7EPE5

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.000340

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.000175 AC: 30 AN: 171280 AF XY: 0.000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000355 AC: 473 AN: 1331172 Hom.: 0 Cov.: 32 AF XY: 0.000340 AC XY: 225 AN XY: 661710

African (AFR) AF: 0.0000738 AC: 2 AN: 27118

American (AMR) AF: 0.0000903 AC: 3 AN: 33234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22036

East Asian (EAS) AF: 0.00 AC: 0 AN: 28790

South Asian (SAS) AF: 0.00 AC: 0 AN: 73984

European-Finnish (FIN) AF: 0.0000222 AC: 1 AN: 45008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3660

European-Non Finnish (NFE) AF: 0.000429 AC: 448 AN: 1044310

Other (OTH) AF: 0.000358 AC: 19 AN: 53032

GnomAD4 genome AF: 0.000185 AC: 28 AN: 151164 Hom.: 0 Cov.: 33 AF XY: 0.000163 AC XY: 12 AN XY: 73796

African (AFR) AF: 0.0000726 AC: 3 AN: 41308

American (AMR) AF: 0.0000659 AC: 1 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000340 AC: 23 AN: 67702

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

Alfa AF: 0.000302 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.000117 AC: 14

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.097	T
Polyphen		0.20	B
Vest4		0.26
MVP		0.68
MPC		2.0
ClinPred		0.34	T
GERP RS		0.22
PromoterAI		0.12	Neutral
Varity_R		0.28
gMVP		0.44
Mutation Taster		=87/13	polymorphism

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: rs202128106; hg19: chr18-12308316; COSMIC: COSV58352970; COSMIC: COSV58352970;