chr18-12325104-C-A

Variant names:

• chr18-12325104-C-A
• NM_032525.3:c.315C>A

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.315C>A​(p.His105Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB6 NM_032525.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.712
• 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, 0.911

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.315C>A	p.His105Gln	missense	Exon 4 of 4	NP_115914.1	Q9BUF5
	TUBB6	NM_001303524.1		c.315C>A	p.His105Gln	missense	Exon 5 of 5	NP_001290453.1	Q9BUF5
	TUBB6	NM_001303526.2		c.204C>A	p.His68Gln	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.315C>A	p.His105Gln	missense	Exon 4 of 4	ENSP00000318697.4	Q9BUF5
	TUBB6	ENST00000591909.5	TSL:1	c.278-4042C>A		intron	N/A	ENSP00000465040.1	K7EJ64
	TUBB6	ENST00000586810.5	TSL:1	n.*356C>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000467348.1	K7EPE5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		0.71
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.80		Gain of sheet (P = 0.1208)
MVP		0.94
MPC		2.1
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.88
gMVP		0.93

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

hg19: chr18-12325103;