rs1555631383

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-42613931-C-T
• chr17-42613931-C-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 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). ClinVar reports functional evidence for this variant: "SCV003461818: Experimental studies have shown that this missense change affects TUBG1 function (PMID:31086189).". 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: 2 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003461818: Experimental studies have shown that this missense change affects TUBG1 function (PMID: 31086189).
• 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

Sel.	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

Sel.	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	P23258
	TUBG1	ENST00000681413.1		c.776C>T	p.Ser259Leu	missense	Exon 8 of 11	ENSP00000505664.1	A0A7P0T9G6
	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

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;