22-18110861-CAGCGATGGTG-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_018943.3(TUBA8):c.-2_3+5del variant causes a splice donor, splice donor region, coding sequence, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,394,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TUBA8 NM_018943.3 splice_donor, splice_donor_region, coding_sequence, 5_prime_UTR, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.043703705 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.5, offset of -29, new splice context is: gagGTgcgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBA8	NM_018943.3	c.-2_3+5del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	1/5	ENST00000330423.8
TUBA8	NM_001193414.2	c.-196+25_-196+34del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBA8	ENST00000330423.8	c.-2_3+5del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, 5_prime_UTR_variant, intron_variant	1/5	1	NM_018943.3	P1
	ENST00000623543.1	n.20284_20293del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000132 AC: 2 AN: 151680 Hom.: 0 AF XY: 0.0000244 AC XY: 2 AN XY: 81826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000785

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394582 Hom.: 0 AF XY: 0.00000290 AC XY: 2 AN XY: 689138

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000547

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 30, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1916347). This variant has not been reported in the literature in individuals affected with TUBA8-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change affects the initiator methionine of the TUBA8 mRNA. The next in-frame methionine is located at codon 67. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1160947614; hg19: chr22-18593627;