2-101007916-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001330348.2(TBC1D8):c.3373T>C(p.Ser1125Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000027 ( 0 hom. )

Consequence

TBC1D8
NM_001330348.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.84

Variant links:

Genes affected

TBC1D8 (HGNC:17791): (TBC1 domain family member 8) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D8 links:

RPL31 (HGNC:10334): (ribosomal protein L31) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L31E family of ribosomal proteins. It is located in the cytoplasm. Higher levels of expression of this gene in familial adenomatous polyps compared to matched normal tissues have been observed. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RPL31 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047515363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TBC1D8	NM_001330348.2 linkuse as main transcript	c.3373T>C	p.Ser1125Pro	missense_variant	20/20	ENST00000409318.2
TBC1D8	NM_001102426.3 linkuse as main transcript	c.3328T>C	p.Ser1110Pro	missense_variant	20/20
RPL31	NM_001098577.3 linkuse as main transcript	c.346+1845A>G		intron_variant
TBC1D8	NR_138475.2 linkuse as main transcript	n.3339T>C		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D8	ENST00000409318.2 linkuse as main transcript	c.3373T>C	p.Ser1125Pro	missense_variant	20/20	5	NM_001330348.2	A1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249248

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.3328T>C (p.S1110P) alteration is located in exon 20 (coding exon 20) of the TBC1D8 gene. This alteration results from a T to C substitution at nucleotide position 3328, causing the serine (S) at amino acid position 1110 to be replaced by a proline (P). 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

0.060

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.67

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.22

T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.47

N;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.016

Sift

Benign

0.29

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.0

B;.

Vest4

0.053

MutPred

0.33

Loss of helix (P = 0.0076);.;

MVP

0.13

MPC

0.30

ClinPred

0.082

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over