rs113714009

Variant names:

• chr22-18111053-A-G
• rs113714009
• NM_018943.3:c.3+185A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018943.3(TUBA8):​c.3+185A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 828,038 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: TUBA8 NM_018943.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.148
• 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: AR, Unknown Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000288683 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-18111053-A-G is Benign according to our data. Variant chr22-18111053-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1216902.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 = 0.00904 (1375/152168) while in subpopulation AFR AF = 0.0261 (1086/41552). AF 95% confidence interval is 0.0248. There are 17 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	NM_018943.3	MANE Select	c.3+185A>G		intron	N/A	NP_061816.1	Q9NY65-1
	TUBA8	NM_001193414.2		c.-196+214A>G		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.3+185A>G		intron	N/A	ENSP00000333326.3	Q9NY65-1
	ENSG00000288683	ENST00000474897.6	TSL:5	n.815-10426A>G		intron	N/A	ENSP00000434235.2	E9PRC5
	TUBA8	ENST00000901607.1		c.3+185A>G		intron	N/A	ENSP00000571666.1

Frequencies

GnomAD3 genomes AF: 0.00897 AC: 1364 AN: 152050 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.00199 AC: 1343 AN: 675870 Hom.: 9 Cov.: 9 AF XY: 0.00175 AC XY: 612 AN XY: 350178

African (AFR) AF: 0.0258 AC: 448 AN: 17394

American (AMR) AF: 0.00656 AC: 196 AN: 29858

Ashkenazi Jewish (ASJ) AF: 0.00670 AC: 119 AN: 17752

East Asian (EAS) AF: 0.00 AC: 0 AN: 31744

South Asian (SAS) AF: 0.000138 AC: 8 AN: 57972

European-Finnish (FIN) AF: 0.0000320 AC: 1 AN: 31234

Middle Eastern (MID) AF: 0.00708 AC: 18 AN: 2542

European-Non Finnish (NFE) AF: 0.000860 AC: 390 AN: 453612

Other (OTH) AF: 0.00483 AC: 163 AN: 33762

GnomAD4 genome AF: 0.00904 AC: 1375 AN: 152168 Hom.: 17 Cov.: 32 AF XY: 0.00863 AC XY: 642 AN XY: 74396

African (AFR) AF: 0.0261 AC: 1086 AN: 41552

American (AMR) AF: 0.0102 AC: 156 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 67958

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.00763 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.25
PhyloP100		-0.15
PromoterAI		0.083	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113714009; hg19: chr22-18593819;