rs1554786802

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 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 (★★).

• 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

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

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 492939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TUBB4B	NM_006088.6	c.1171C>T	p.Arg391Cys	missense_variant	Exon 4 of 4	ENST00000340384.5	NP_006079.1
CIMIP2A	NM_001001710.3	c.*311G>A		downstream_gene_variant		ENST00000344774.6	NP_001001710.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TUBB4B	ENST00000340384.5	c.1171C>T	p.Arg391Cys	missense_variant	Exon 4 of 4	1	NM_006088.6	ENSP00000341289.4
TUBB4B	ENST00000604929.1	n.1718C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1
FAM166A	ENST00000344774.6	c.*311G>A		downstream_gene_variant		1	NM_001001710.3	ENSP00000344729.4
FAM166A	ENST00000471784.2	n.*195G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis with early-onset deafness Pathogenic:5

Apr 15, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 10, 2022

Department of Medical Genetics, University of Pecs

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

TUBB4B c.1171 C>T variant results in arginine to cysteine amino acid change at 390 position. Classification of the variant according to the ACMG guidelines provide moderate/strong evidence of pathogenicity. This variant has been reported in a Danish boy by Luscan et al (PMID: 29198720). Besides, this variant was observed in three members of a Hungarian family with Leber congenital amaurosis with early-onset deafness (LCAEOD) (under publication). The variant was assumed de novo with confirmation of only maternity (PM6). In vitro functional study of Luscan et al provide evidence that the variant has damaging effect on the gene product (PS3). The c.1171C>T variant affects the Arg390 amino acid residue where a different missense change (c.1172G>A) has been found to be pathogenic before (PM5). The c.1171C>T variant is absent from large general reference population and disease cohorts (1000Genomes, dbSNP, gnomAD: n>120 000 exomes and >15 000 genomes) (PM2). In silico prediction tools like PolyPhen, Provean and MutationTaster provide evidence that the c.1171C>T variant is a protein damaging, disease-causing variant (PP3). For these reasons, this variant was classified as a Likely Pathogenic variant for the autosomal dominant LCAEOD. -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Leber congenital amaurosis with early-onset deafness, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/29198720). PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/29198720). PM5 => Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS4_Supporting+PP4+PP1+PM6_Supporting+PM5+PP2+PP3_Moderate -

not provided Pathogenic:1

Jan 17, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect that results in diminished microtubule depolarization kinetics resulting in decreased microtubule growth rate (PMID: 29198720); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32681585, 29198720, 35240325, 36460718, 34021019) -

Computational scores

Source: dbNSFP v4.3

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
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

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: rs1554786802; hg19: chr9-140137841;