NM_018943.3:c.748G>A

Variant names:

• chr22-18126726-G-A
• rs145621219
• NM_018943.3:c.748G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS2

The NM_018943.3(TUBA8):​c.748G>A​(p.Val250Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,614,128 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (24 hom.)
• Consequence: TUBA8 NM_018943.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 10.0
• Publications: 9 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: Benign. The variant received -15 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.01633808).
• BP6: Variant 22-18126726-G-A is Benign according to our data. Variant chr22-18126726-G-A is described in ClinVar as Benign. ClinVar VariationId is 137851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 24 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018943.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	NM_018943.3	MANE Select	c.748G>A	p.Val250Met	missense	Exon 4 of 5	NP_061816.1
	TUBA8	NM_001193414.2		c.550G>A	p.Val184Met	missense	Exon 4 of 5	NP_001180343.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	ENST00000330423.8	TSL:1 MANE Select	c.748G>A	p.Val250Met	missense	Exon 4 of 5	ENSP00000333326.3
	TUBA8	ENST00000416740.2	TSL:1	c.550G>A	p.Val184Met	missense	Exon 4 of 5	ENSP00000412646.2
	ENSG00000288683	ENST00000474897.6	TSL:5	n.*638G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 448 AN: 152116 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00345 AC: 868 AN: 251486 AF XY: 0.00318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00194 AC: 2838 AN: 1461894 Hom.: 24 Cov.: 31 AF XY: 0.00197 AC XY: 1434 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0238 AC: 1271 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00125 AC: 1387 AN: 1112012

Other (OTH) AF: 0.00166 AC: 100 AN: 60396

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152234 Hom.: 1 Cov.: 31 AF XY: 0.00382 AC XY: 284 AN XY: 74420

African (AFR) AF: 0.0000481 AC: 2 AN: 41540

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0227 AC: 241 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00269 AC: 183 AN: 68016

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00250 Hom.: 6

Bravo AF: 0.00109

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00314 AC: 381

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TUBA8: PP3, BS1, BS2

not specified Benign:1

Sep 15, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TUBA8-related disorder Benign:1

Apr 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		10
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.026	D
Polyphen		0.99	D
Vest4		0.86
MVP		0.99
MPC		0.88
ClinPred		0.066	T
GERP RS		5.7
PromoterAI		0.011	Neutral
Varity_R		0.48
gMVP		0.64
Mutation Taster		=85/15	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: rs145621219; hg19: chr22-18609493;