2-101007861-C-T

Variant names:

• chr2-101007861-C-T
• rs749419550
• NM_001330348.2:c.3428G>A

Variant summary

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

The NM_001330348.2(TBC1D8):​c.3428G>A​(p.Ser1143Asn) 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 benign outcome for this variant. 13/21 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)
• Consequence: TBC1D8 NM_001330348.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.13

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]

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]

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=0.10609263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D8	NM_001330348.2	c.3428G>A	p.Ser1143Asn	missense_variant	Exon 20 of 20	ENST00000409318.2	NP_001317277.1
TBC1D8	NM_001102426.3	c.3383G>A	p.Ser1128Asn	missense_variant	Exon 20 of 20		NP_001095896.1
RPL31	NM_001098577.3	c.346+1790C>T		intron_variant	Intron 4 of 4		NP_001092047.1
TBC1D8	NR_138475.2	n.3394G>A		non_coding_transcript_exon_variant	Exon 19 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D8	ENST00000409318.2	c.3428G>A	p.Ser1143Asn	missense_variant	Exon 20 of 20	5	NM_001330348.2	ENSP00000386856.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249000 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3383G>A (p.S1128N) alteration is located in exon 20 (coding exon 20) of the TBC1D8 gene. This alteration results from a G to A substitution at nucleotide position 3383, causing the serine (S) at amino acid position 1128 to be replaced by an asparagine (N). 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	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	T;.
Eigen	Benign	0.025
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.059
Sift	Benign	0.047	D;D
Sift4G	Benign	0.23	T;T
Polyphen		0.79	P;.
Vest4		0.076
MutPred		0.18		Gain of relative solvent accessibility (P = 0.0215);.;
MVP		0.26
MPC		0.23
ClinPred		0.54	D
GERP RS		3.3
Varity_R		0.094
gMVP		0.27

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: rs749419550; hg19: chr2-101624323;