rs115847686

chr22-18124179-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018943.3(TUBA8):c.250C>T(p.Arg84Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,614,136 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R84H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (7 hom.)
• Consequence: TUBA8 NM_018943.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.09

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010679781).
• BP6: Variant 22-18124179-C-T is Benign according to our data. Variant chr22-18124179-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 160171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0053 (807/152260) while in subpopulation AFR AF= 0.0186 (771/41542). AF 95% confidence interval is 0.0175. There are 7 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA8	NM_018943.3	c.250C>T	p.Arg84Cys	missense_variant	3/5	ENST00000330423.8
TUBA8	NM_001193414.2	c.52C>T	p.Arg18Cys	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA8	ENST00000330423.8	c.250C>T	p.Arg84Cys	missense_variant	3/5	1	NM_018943.3	P1
	ENST00000623543.1	n.6976G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 804 AN: 152142 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00137 AC: 345 AN: 251446 Hom.: 1 AF XY: 0.000986 AC XY: 134 AN XY: 135902

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000553 AC: 809 AN: 1461876 Hom.: 7 Cov.: 30 AF XY: 0.000470 AC XY: 342 AN XY: 727240

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00530 AC: 807 AN: 152260 Hom.: 7 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74446

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00228 Hom.: 4

Bravo AF: 0.00606

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00166 AC: 202

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D;D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Uncertain	-0.031	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.0	D;D;D;D
REVEL	Uncertain	0.60
Sift4G	Uncertain	0.038	D;T;T;T
Polyphen		0.98, 0.10	.;.;D;B
Vest4		0.60, 0.62
MVP		0.87
MPC		0.83
ClinPred		0.099	T
GERP RS		4.1
Varity_R		0.66
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs115847686; hg19: chr22-18606946;