chr17-42614407-A-C

Position:

• chr17-42614407-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001070.5(TUBG1):​c.991A>C​(p.Thr331Pro) variant causes a missense change. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBG1 NM_001070.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.19

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TUBG1. . Gene score misZ 4.1551 (greater than the threshold 3.09). Trascript score misZ 5.8568 (greater than threshold 3.09). GenCC has associacion of gene with lissencephaly spectrum disorders, complex cortical dysplasia with other brain malformations 4.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 17-42614407-A-C is Pathogenic according to our data. Variant chr17-42614407-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 65399.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TUBG1	NM_001070.5	c.991A>C	p.Thr331Pro	missense_variant	9/11	ENST00000251413.8	NP_001061.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TUBG1	ENST00000251413.8	c.991A>C	p.Thr331Pro	missense_variant	9/11	1	NM_001070.5	ENSP00000251413.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Complex cortical dysplasia with other brain malformations 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.072	T
Polyphen		0.99	D
Vest4		0.84
MutPred		0.50		Gain of catalytic residue at P330 (P = 0.0138);
MVP		0.87
MPC		3.0
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123047; hg19: chr17-40766425;