rs151102020

Variant names:

• chr22-18126945-G-A
• rs151102020
• NM_018943.3:c.967G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-18126945-G-A
• chr22-18126945-G-C
• chr22-18126945-G-T

Variant summary

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

The NM_018943.3(TUBA8):​c.967G>A​(p.Val323Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,613,272 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V323L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: TUBA8 NM_018943.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 10.0
• Publications: 3 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 0 ACMG points.

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.967G>A	p.Val323Met	missense	Exon 4 of 5	NP_061816.1
	TUBA8	NM_001193414.2		c.769G>A	p.Val257Met	missense	Exon 4 of 5	NP_001180343.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBA8	ENST00000330423.8	TSL:1 MANE Select	c.967G>A	p.Val323Met	missense	Exon 4 of 5	ENSP00000333326.3
	TUBA8	ENST00000416740.2	TSL:1	c.769G>A	p.Val257Met	missense	Exon 4 of 5	ENSP00000412646.2
	ENSG00000288683	ENST00000474897.6	TSL:5	n.*857G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000434235.2

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152072 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000327 AC: 82 AN: 250692 AF XY: 0.000399

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000300

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000565

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000322 AC: 471 AN: 1461082 Hom.: 1 Cov.: 31 AF XY: 0.000333 AC XY: 242 AN XY: 726758

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.000336 AC: 15 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.000384 AC: 10 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86166

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53404

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.000350 AC: 389 AN: 1111528

Other (OTH) AF: 0.000613 AC: 37 AN: 60334

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.000282 AC XY: 21 AN XY: 74412

African (AFR) AF: 0.000145 AC: 6 AN: 41520

American (AMR) AF: 0.000393 AC: 6 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000448 Hom.: 1

Bravo AF: 0.000295

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.00147

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Macrothrombocytopenia, isolated, 2, autosomal dominant (1)
-	1	-	not specified (1)
-	1	-	Polymicrogyria with optic nerve hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.84
MVP		0.98
MPC		0.89
ClinPred		0.14	T
GERP RS		5.7
PromoterAI		0.024	Neutral
Varity_R		0.68
gMVP		0.75
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs151102020; hg19: chr22-18609712;