NM_001330348.2:c.3191G>A

Variant names:

• chr2-101008098-C-T
• rs888458057
• NM_001330348.2:c.3191G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001330348.2(TBC1D8):​c.3191G>A​(p.Arg1064Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1064W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TBC1D8 NM_001330348.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.627
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03286755).
• BP6: Variant 2-101008098-C-T is Benign according to our data. Variant chr2-101008098-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3453626.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3191G>A	p.Arg1064Gln	missense	Exon 20 of 20	NP_001317277.1	J3KQ40
	TBC1D8	NM_001102426.3		c.3146G>A	p.Arg1049Gln	missense	Exon 20 of 20	NP_001095896.1	O95759-1
	RPL31	NM_001098577.3		c.346+2027C>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.3191G>A	p.Arg1064Gln	missense	Exon 20 of 20	ENSP00000386856.1	J3KQ40
	TBC1D8	ENST00000376840.8	TSL:1	c.3146G>A	p.Arg1049Gln	missense	Exon 20 of 20	ENSP00000366036.4	O95759-1
	TBC1D8	ENST00000870702.1		c.3200G>A	p.Arg1067Gln	missense	Exon 20 of 20	ENSP00000540761.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248912 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000116 AC: 17 AN: 1461556 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 727036

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111748

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0060
DANN	Benign	0.80
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.63
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.019
Sift	Benign	0.72	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.052
MutPred		0.10		Loss of loop (P = 0.0804)
MVP		0.095
MPC		0.28
ClinPred		0.018	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.042
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs888458057; hg19: chr2-101624560;