rs540694342

Variant names:

• chr22-18110385-C-T
• rs540694342
• ENST00000474897.6:n.815-11094C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000474897.6(ENSG00000288683):​n.815-11094C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 214,414 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: ENSG00000288683 ENST00000474897.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0130
• Publications: 0 publications found

Genes affected

ENSG00000288683 (HGNC:):

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: AR, Unknown Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-18110385-C-T is Benign according to our data. Variant chr22-18110385-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1178498.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0054 (823/152334) while in subpopulation AFR AF = 0.0186 (774/41584). AF 95% confidence interval is 0.0175. There are 5 homozygotes in GnomAd4. There are 403 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000474897.6. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288683	ENST00000474897.6	TSL:5	n.815-11094C>T		intron	N/A	ENSP00000434235.2	E9PRC5
	TUBA8	ENST00000901606.1		c.-481C>T		5_prime_UTR	Exon 1 of 5	ENSP00000571665.1
	TUBA8	ENST00000901605.1		c.-481C>T		5_prime_UTR	Exon 1 of 5	ENSP00000571664.1

Frequencies

GnomAD3 genomes AF: 0.00539 AC: 820 AN: 152216 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.000258 AC: 16 AN: 62080 Hom.: 0 Cov.: 0 AF XY: 0.000246 AC XY: 8 AN XY: 32480

African (AFR) AF: 0.0127 AC: 6 AN: 472

American (AMR) AF: 0.000923 AC: 1 AN: 1084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1458

East Asian (EAS) AF: 0.00 AC: 0 AN: 920

South Asian (SAS) AF: 0.0000992 AC: 1 AN: 10082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000998 AC: 4 AN: 40076

Other (OTH) AF: 0.00108 AC: 4 AN: 3700

GnomAD4 genome AF: 0.00540 AC: 823 AN: 152334 Hom.: 5 Cov.: 32 AF XY: 0.00541 AC XY: 403 AN XY: 74486

African (AFR) AF: 0.0186 AC: 774 AN: 41584

American (AMR) AF: 0.00209 AC: 32 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00430 Hom.: 0

Bravo AF: 0.00580

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.4
DANN	Benign	0.90
PhyloP100		0.013
PromoterAI		0.12	Neutral

Splicing

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

Other links and lift over

dbSNP: rs540694342; hg19: chr22-18593151;