NM_006088.6:c.1171C>T

Variant names:

• chr9-137243389-C-T
• rs1554786802
• NM_006088.6:c.1171C>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_006088.6(TUBB4B):​c.1171C>T​(p.Arg391Cys) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002064316: "In vitro functional study of Luscan et al provide evidence that the variant has damaging effect on the gene product (PS3)." PMID:29198720" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB4B NM_006088.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.85
• Publications: 1 publications found

Genes affected

TUBB4B (HGNC:20771): (tubulin beta 4B class IVb) Enables double-stranded RNA binding activity. Predicted to be involved in microtubule cytoskeleton organization and mitotic cell cycle. Located in microtubule. Implicated in Leber congenital amaurosis with early-onset deafness. [provided by Alliance of Genome Resources, Apr 2022]

CIMIP2A (HGNC:33818): (ciliary microtubule inner protein 2A) Located in ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002064316: "In vitro functional study of Luscan et al provide evidence that the variant has damaging effect on the gene product (PS3)." PMID: 29198720; SCV001985785: Published functional studies demonstrate a damaging effect that results in diminished microtubule depolarization kinetics resulting in decreased microtubule growth rate (PMID: 29198720)
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-137243390-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 492938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.4977 (above the threshold of 3.09). Trascript score misZ: 6.5739 (above the threshold of 3.09). GenCC associations: The gene is linked to Leber congenital amaurosis with early-onset deafness, TUBB4B-related ciliopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 9-137243389-C-T is Pathogenic according to our data. Variant chr9-137243389-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 492939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006088.6. 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
	TUBB4B	NM_006088.6	MANE Select	c.1171C>T	p.Arg391Cys	missense	Exon 4 of 4	NP_006079.1	P68371
	CIMIP2A	NM_001001710.3	MANE Select	c.*311G>A		downstream_gene	N/A	NP_001001710.1	Q6J272-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4B	ENST00000340384.5	TSL:1 MANE Select	c.1171C>T	p.Arg391Cys	missense	Exon 4 of 4	ENSP00000341289.4	P68371
	TUBB4B	ENST00000604929.1	TSL:1	n.1718C>T		non_coding_transcript_exon	Exon 3 of 3
	TUBB4B	ENST00000938213.1		c.1162C>T	p.Arg388Cys	missense	Exon 4 of 4	ENSP00000608272.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Leber congenital amaurosis with early-onset deafness (5)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		3.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.84
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.85		Loss of MoRF binding (P = 0.0094)
MVP		0.96
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.83
gMVP		0.96
Mutation Taster		=15/85	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: rs1554786802; hg19: chr9-140137841;