chr5-179865348-G-A

Position:

• chr5-179865348-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015043.4(TBC1D9B):​c.2927C>T​(p.Thr976Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBC1D9B NM_015043.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

Genes affected

TBC1D9B (HGNC:29097): (TBC1 domain family member 9B) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D9B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1651825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D9B	NM_015043.4	c.2927C>T	p.Thr976Ile	missense_variant	20/21	ENST00000355235.8	NP_055858.2
TBC1D9B	NM_198868.3	c.2978C>T	p.Thr993Ile	missense_variant	21/22		NP_942568.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D9B	ENST00000355235.8	c.2927C>T	p.Thr976Ile	missense_variant	20/21	5	NM_015043.4	ENSP00000347375.3
TBC1D9B	ENST00000524222.2	c.188-82C>T		intron_variant		5		ENSP00000428724.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461736 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2021

The c.2978C>T (p.T993I) alteration is located in exon 21 (coding exon 21) of the TBC1D9B gene. This alteration results from a C to T substitution at nucleotide position 2978, causing the threonine (T) at amino acid position 993 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	.;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.058	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.26, 0.17	.;B;B
Vest4		0.25
MutPred		0.19		.;.;Loss of phosphorylation at T993 (P = 0.0165);
MVP		0.53
MPC		0.21
ClinPred		0.69	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.21

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-179292348;