NM_032525.3:c.361C>G

Variant names:

• chr18-12325150-C-G
• rs1424404112
• NM_032525.3:c.361C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032525.3(TUBB6):​c.361C>G​(p.Arg121Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TUBB6 NM_032525.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.348
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

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.361C>G	p.Arg121Gly	missense	Exon 4 of 4	NP_115914.1	Q9BUF5
	TUBB6	NM_001303524.1		c.361C>G	p.Arg121Gly	missense	Exon 5 of 5	NP_001290453.1	Q9BUF5
	TUBB6	NM_001303526.2		c.250C>G	p.Arg84Gly	missense	Exon 3 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.361C>G	p.Arg121Gly	missense	Exon 4 of 4	ENSP00000318697.4	Q9BUF5
	TUBB6	ENST00000591909.5	TSL:1	c.278-3996C>G		intron	N/A	ENSP00000465040.1	K7EJ64
	TUBB6	ENST00000586810.5	TSL:1	n.*402C>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000467348.1	K7EPE5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		0.35
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.76		Loss of methylation at K122 (P = 0.0478)
MVP		0.85
MPC		2.3
ClinPred		1.0	D
GERP RS		-5.2
Varity_R		0.82
gMVP		0.97

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: rs1424404112; hg19: chr18-12325149;