NM_001070.5:c.776C>T

Variant names:

• chr17-42613931-C-T
• rs1555631383
• NM_001070.5:c.776C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001070.5(TUBG1):​c.776C>T​(p.Ser259Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S259S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBG1 NM_001070.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.87
• Publications: 1 publications found

Genes affected

TUBG1 (HGNC:12417): (tubulin gamma 1) This gene encodes a member of the tubulin superfamily. The encoded protein localizes to the centrosome where it binds to microtubules as part of a complex referred to as the gamma-tubulin ring complex. The protein mediates microtubule nucleation and is required for microtubule formation and progression of the cell cycle. A pseudogene of this gene is found on chromosome 7. [provided by RefSeq, Jan 2009]

TUBG1 Gene-Disease associations (from GenCC):

• lissencephaly spectrum disorders

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• complex cortical dysplasia with other brain malformations 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the TUBG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 4.1551 (above the threshold of 3.09). Trascript score misZ: 5.8568 (above the threshold of 3.09). GenCC associations: The gene is linked to complex cortical dysplasia with other brain malformations 4, lissencephaly spectrum disorders.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 17-42613931-C-T is Pathogenic according to our data. Variant chr17-42613931-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437135.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001070.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBG1	NM_001070.5	MANE Select	c.776C>T	p.Ser259Leu	missense	Exon 8 of 11	NP_001061.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBG1	ENST00000251413.8	TSL:1 MANE Select	c.776C>T	p.Ser259Leu	missense	Exon 8 of 11	ENSP00000251413.2
	TUBG1	ENST00000681413.1		c.776C>T	p.Ser259Leu	missense	Exon 8 of 11	ENSP00000505664.1
	TUBG1	ENST00000951125.1		c.773C>T	p.Ser258Leu	missense	Exon 8 of 11	ENSP00000621184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Lissencephaly (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.93	P
Vest4		0.92
MutPred		0.66		Gain of glycosylation at T263 (P = 0.2561)
MVP		0.97
MPC		1.9
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.81
gMVP		0.98
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs1555631383; hg19: chr17-40765949;