22-18110861-CAGCGATGGTG-C

Variant names:

• chr22-18110861-CAGCGATGGTG-C
• rs1160947614
• NM_018943.3:c.-2_3+5delCGATGGTGAG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_018943.3(TUBA8):​c.-2_3+5delCGATGGTGAG variant causes a splice donor, splice region, 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_region, 5_prime_UTR, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03
• Publications: 0 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.044444446 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	NM_018943.3	MANE Select	c.-2_3+5delCGATGGTGAG	p.Met1fs	frameshift start_lost splice_region	Exon 1 of 5	NP_061816.1	Q9NY65-1
	TUBA8	NM_018943.3	MANE Select	c.-2_3+5delCGATGGTGAG		splice_donor splice_region 5_prime_UTR intron	Exon 1 of 5	NP_061816.1	Q9NY65-1
	TUBA8	NM_001193414.2		c.-196+25_-196+34delCGATGGTGAG		intron	N/A	NP_001180343.1	Q9NY65-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	ENST00000330423.8	TSL:1 MANE Select	c.-2_3+5delCGATGGTGAG	p.Met1fs	frameshift start_lost splice_region	Exon 1 of 5	ENSP00000333326.3	Q9NY65-1
	TUBA8	ENST00000330423.8	TSL:1 MANE Select	c.-2_3+5delCGATGGTGAG		splice_donor splice_region 5_prime_UTR intron	Exon 1 of 5	ENSP00000333326.3	Q9NY65-1
	ENSG00000288683	ENST00000474897.6	TSL:5	n.815-10615_815-10606delCGATGGTGAG		intron	N/A	ENSP00000434235.2	E9PRC5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000132 AC: 2 AN: 151680 AF XY: 0.0000244

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32388

American (AMR) AF: 0.0000547 AC: 2 AN: 36572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25204

East Asian (EAS) AF: 0.00 AC: 0 AN: 37040

South Asian (SAS) AF: 0.00 AC: 0 AN: 80014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4328

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084502

Other (OTH) AF: 0.00 AC: 0 AN: 58124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=42/158	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1160947614; hg19: chr22-18593627;