rs1554786802

chr9-137243389-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• 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 [Likely_pathogenic]. Clinvar id is 492938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TUBB4B
• 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 492939.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBB4B	NM_006088.6	c.1171C>T	p.Arg391Cys	missense_variant	4/4	ENST00000340384.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBB4B	ENST00000340384.5	c.1171C>T	p.Arg391Cys	missense_variant	4/4	1	NM_006088.6	P1
TUBB4B	ENST00000604929.1	n.1718C>T		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leber congenital amaurosis with early-onset deafness Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Department of Medical Genetics, University of Pecs	Jan 10, 2022	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. -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 15, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 26, 2021

Published functional studies demonstrate a damaging effect that results in diminished microtubule depolarization kinetics resulting in decreased microtubule growth rate (Luscan et al., 2017); A different missense change at this residue (R391H) has been reported in the published literature (Luscan et al., 2017) in multiple families with retinal disease and hearing loss; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 29198720, 32681585) -

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
MutationTaster	Benign	1.0	D
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;