2-101011463-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001330348.2(TBC1D8):c.2905G>A(p.Gly969Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,398 control chromosomes in the GnomAD database, including 13,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.092 (869 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12477 hom.)
• Consequence: TBC1D8 NM_001330348.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.02

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014540851).
• BP6: Variant 2-101011463-C-T is Benign according to our data. Variant chr2-101011463-C-T is described in ClinVar as [Benign]. Clinvar id is 1256912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D8	NM_001330348.2	c.2905G>A	p.Gly969Arg	missense_variant	18/20	ENST00000409318.2
TBC1D8	NM_001102426.3	c.2860G>A	p.Gly954Arg	missense_variant	18/20
RPL31	NM_001098577.3	c.346+5392C>T		intron_variant
TBC1D8	NR_138475.2	n.2871G>A		non_coding_transcript_exon_variant	17/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D8	ENST00000409318.2	c.2905G>A	p.Gly969Arg	missense_variant	18/20	5	NM_001330348.2	A1

Frequencies

GnomAD3 genomes AF: 0.0920 AC: 13972 AN: 151810 Hom.: 869 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0939

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.0595

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.0997

GnomAD3 exomes AF: 0.0978 AC: 24376 AN: 249208 Hom.: 1597 AF XY: 0.100 AC XY: 13513 AN XY: 135192

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.0627

Gnomad ASJ exome AF: 0.0580

Gnomad EAS exome AF: 0.000389

Gnomad SAS exome AF: 0.0654

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.123 AC: 179841 AN: 1461470 Hom.: 12477 Cov.: 32 AF XY: 0.121 AC XY: 88184 AN XY: 727030

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.0658

Gnomad4 ASJ exome AF: 0.0565

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.0644

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.103

GnomAD4 genome AF: 0.0920 AC: 13970 AN: 151928 Hom.: 869 Cov.: 32 AF XY: 0.0923 AC XY: 6848 AN XY: 74226

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.0937

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.0593

Gnomad4 FIN AF: 0.154

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.0987

Alfa AF: 0.119 Hom.: 2523

Bravo AF: 0.0850

TwinsUK AF: 0.144 AC: 534

ALSPAC AF: 0.143 AC: 552

ESP6500AA AF: 0.0262 AC: 101

ESP6500EA AF: 0.130 AC: 1073

ExAC AF: 0.0984 AC: 11890

Asia WGS AF: 0.0240 AC: 86 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.131

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2019

This variant is associated with the following publications: (PMID: 29083408) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	2.1e-7	P;P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.13
Sift	Benign	0.069	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.015	B;.
Vest4		0.16
MutPred		0.26		Gain of loop (P = 0.0097);.;
MPC		0.45
ClinPred		0.028	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1062062; hg19: chr2-101627925; COSMIC: COSV51821651; COSMIC: COSV51821651;