chr6-30723727-A-T

Position:

• chr6-30723727-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_178014.4(TUBB):​c.665A>T​(p.Tyr222Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y222Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TUBB NM_178014.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.01

Genes affected

TUBB (HGNC:20778): (tubulin beta class I) This gene encodes a beta tubulin protein. This protein forms a dimer with alpha tubulin and acts as a structural component of microtubules. Mutations in this gene cause cortical dysplasia, complex, with other brain malformations 6. Alternative splicing results in multiple splice variants. There are multiple pseudogenes for this gene on chromosomes 1, 6, 7, 8, 9, and 13. [provided by RefSeq, Jun 2014]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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), TUBB. . Gene score misZ 5.6252 (greater than the threshold 3.09). Trascript score misZ 8.3435 (greater than threshold 3.09). GenCC has associacion of gene with multiple benign circumferential skin creases on limbs 1, complex cortical dysplasia with other brain malformations 6, multiple benign circumferential skin creases on limbs, TUBB3-related tubulinopathy.
• PP5: Variant 6-30723727-A-T is Pathogenic according to our data. Variant chr6-30723727-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 218926.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in UniProt as null. Variant chr6-30723727-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB	NM_178014.4	c.665A>T	p.Tyr222Phe	missense_variant	4/4	ENST00000327892.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB	ENST00000327892.13	c.665A>T	p.Tyr222Phe	missense_variant	4/4	1	NM_178014.4	P1
	ENST00000607476.1	n.151T>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Multiple benign circumferential skin creases on limbs 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.42
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.47	P;.;.;.
Vest4		0.75
MutPred		0.62		Loss of catalytic residue at L217 (P = 0.1155);.;.;.;
MVP		0.87
MPC		1.7
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.82
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs864321677; hg19: chr6-30691504;