9-137243389-CGC-TGT

Variant names:

• chr9-137243389-CGC-TGT
• NM_006088.6:c.1171_1173delCGCinsTGT
• TUBB4B p.Arg391Cys

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1_Very_Strong PM5 PP2 PP3

The NM_006088.6(TUBB4B):​c.1171_1173delCGCinsTGT​(p.Arg391Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic 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: Not reported in ClinVar
• Conservation: PhyloP100: 7.97
• Publications: 0 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 12 ACMG points.

• PS1: Transcript NM_006088.6 (TUBB4B) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1171_1173delCGCinsTGT	p.Arg391Cys	missense	N/A	NP_006079.1	P68371
	CIMIP2A	NM_001001710.3	MANE Select	c.*309_*311delGCGinsACA		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.1171_1173delCGCinsTGT	p.Arg391Cys	missense	N/A	ENSP00000341289.4	P68371
	TUBB4B	ENST00000604929.1	TSL:1	n.1718_1720delCGCinsTGT		non_coding_transcript_exon	Exon 3 of 3
	TUBB4B	ENST00000938213.1		c.1162_1164delCGCinsTGT	p.Arg388Cys	missense	N/A	ENSP00000608272.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-140137841;