2-101011463-C-T

Variant names:

• chr2-101011463-C-T
• rs1062062
• NM_001330348.2:c.2905G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 12/21 in silico tools predict 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.02
• Publications: 16 publications found

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]

RPL31 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1256912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330348.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D8	NM_001330348.2	MANE Select	c.2905G>A	p.Gly969Arg	missense	Exon 18 of 20	NP_001317277.1	J3KQ40
	TBC1D8	NM_001102426.3		c.2860G>A	p.Gly954Arg	missense	Exon 18 of 20	NP_001095896.1	O95759-1
	RPL31	NM_001098577.3		c.346+5392C>T		intron	N/A	NP_001092047.1	P62899-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D8	ENST00000409318.2	TSL:5 MANE Select	c.2905G>A	p.Gly969Arg	missense	Exon 18 of 20	ENSP00000386856.1	J3KQ40
	TBC1D8	ENST00000376840.8	TSL:1	c.2860G>A	p.Gly954Arg	missense	Exon 18 of 20	ENSP00000366036.4	O95759-1
	TBC1D8	ENST00000870702.1		c.2914G>A	p.Gly972Arg	missense	Exon 18 of 20	ENSP00000540761.1

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

GnomAD2 exomes AF: 0.0978 AC: 24376 AN: 249208 AF XY: 0.100

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 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

African (AFR) AF: 0.0184 AC: 615 AN: 33472

American (AMR) AF: 0.0658 AC: 2943 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 1476 AN: 26134

East Asian (EAS) AF: 0.000479 AC: 19 AN: 39700

South Asian (SAS) AF: 0.0644 AC: 5555 AN: 86254

European-Finnish (FIN) AF: 0.152 AC: 8114 AN: 53386

Middle Eastern (MID) AF: 0.0581 AC: 335 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154563 AN: 1111672

Other (OTH) AF: 0.103 AC: 6221 AN: 60362

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

African (AFR) AF: 0.0232 AC: 961 AN: 41456

American (AMR) AF: 0.0937 AC: 1428 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 187 AN: 3468

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5166

South Asian (SAS) AF: 0.0593 AC: 285 AN: 4804

European-Finnish (FIN) AF: 0.154 AC: 1617 AN: 10516

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9138 AN: 67962

Other (OTH) AF: 0.0987 AC: 208 AN: 2108

Alfa AF: 0.114 Hom.: 3364

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.069	T
Sift4G	Benign	0.27	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
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1062062; hg19: chr2-101627925; COSMIC: COSV51821651; COSMIC: COSV51821651;