22-18126936-C-T

Position:

• chr22-18126936-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BP4

The NM_018943.3(TUBA8):​c.958C>T​(p.Arg320Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000526 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (0 hom.)
• Consequence: TUBA8 NM_018943.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.87

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.4061558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA8	NM_018943.3	c.958C>T	p.Arg320Trp	missense_variant	4/5	ENST00000330423.8
TUBA8	NM_001193414.2	c.760C>T	p.Arg254Trp	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA8	ENST00000330423.8	c.958C>T	p.Arg320Trp	missense_variant	4/5	1	NM_018943.3	P1
	ENST00000623543.1	n.4219G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000516 AC: 129 AN: 250082 Hom.: 0 AF XY: 0.000496 AC XY: 67 AN XY: 135166

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00312

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000626

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000557

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000544 AC: 795 AN: 1460522 Hom.: 0 Cov.: 31 AF XY: 0.000553 AC XY: 402 AN XY: 726514

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00300

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000558

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.000533

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74416

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000702 Hom.: 0

Bravo AF: 0.000438

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000654

EpiControl AF: 0.00131

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2023	PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Polymicrogyria with optic nerve hypoplasia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 02, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 26, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.81
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.96
MVP		1.0
MPC		0.91
ClinPred		0.58	D
GERP RS		3.5
Varity_R		0.90
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs140202346; hg19: chr22-18609703; COSMIC: COSV57812737; COSMIC: COSV57812737;