chr22-18126945-G-T

Variant names:

• chr22-18126945-G-T
• rs151102020
• NM_018943.3:c.967G>T

Variant summary

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

The NM_018943.3(TUBA8):​c.967G>T​(p.Val323Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V323M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TUBA8 NM_018943.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 3 publications found

Genes affected

TUBA8 (HGNC:12410): (tubulin alpha 8) This gene encodes a member of the alpha tubulin protein family. Alpha tubulins are one of two core protein families (alpha and beta tubulins) that heterodimerize and assemble to form microtubules. Mutations in this gene are associated with polymicrogyria and optic nerve hypoplasia. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2010]

TUBA8 Gene-Disease associations (from GenCC):

• polymicrogyria with optic nerve hypoplasia

  Inheritance: Unknown, AR Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ENSG00000288683 (HGNC:):

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBA8	NM_018943.3	c.967G>T	p.Val323Leu	missense_variant	Exon 4 of 5	ENST00000330423.8	NP_061816.1
TUBA8	NM_001193414.2	c.769G>T	p.Val257Leu	missense_variant	Exon 4 of 5		NP_001180343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBA8	ENST00000330423.8	c.967G>T	p.Val323Leu	missense_variant	Exon 4 of 5	1	NM_018943.3	ENSP00000333326.3
ENSG00000288683	ENST00000474897.6	n.*857G>T		non_coding_transcript_exon_variant	Exon 8 of 9	5		ENSP00000434235.2
ENSG00000288683	ENST00000474897.6	n.*857G>T		3_prime_UTR_variant	Exon 8 of 9	5		ENSP00000434235.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;D;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.4	.;M;.
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.043	D;D;D
Polyphen		0.60, 0.99	.;P;D
Vest4		0.85
MutPred		0.78		.;.;Loss of methylation at K350 (P = 0.0798);
MVP		0.98
MPC		0.88
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		-0.021	Neutral
Varity_R		0.90
gMVP		0.79
Mutation Taster		=64/36	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: rs151102020; hg19: chr22-18609712;