9-137243199-T-A

Variant names:

• chr9-137243199-T-A
• rs9330200
• NM_006088.6:c.981T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_006088.6(TUBB4B):​c.981T>A​(p.Asp327Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TUBB4B NM_006088.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 2 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]

TUBB4B Gene-Disease associations (from GenCC):

• Leber congenital amaurosis with early-onset deafness

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4B	NM_006088.6	MANE Select	c.981T>A	p.Asp327Glu	missense	Exon 4 of 4	NP_006079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBB4B	ENST00000340384.5	TSL:1 MANE Select	c.981T>A	p.Asp327Glu	missense	Exon 4 of 4	ENSP00000341289.4
	TUBB4B	ENST00000604929.1	TSL:1	n.1528T>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Benign	0.79
DEOGEN2	Benign	0.40	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.29	N
PhyloP100		-1.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.38
Sift4G	Benign	0.55	T
Polyphen		0.0050	B
Vest4		0.78
MutPred		0.79		Gain of ubiquitination at K324 (P = 0.0719)
MVP		0.76
ClinPred		0.12	T
GERP RS		-5.8
Varity_R		0.62
gMVP		0.91
Mutation Taster		=55/45	polymorphism

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: rs9330200; hg19: chr9-140137651;