2-101007870-A-AAAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PM4_Supporting BP6_Moderate BA1

The NM_001330348.2(TBC1D8):c.3418_3419insCTT(p.Thr1139_Phe1140insSer) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,864 control chromosomes in the GnomAD database, including 1,370 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.053 (715 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (655 hom.)
• Consequence: TBC1D8 NM_001330348.2 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0250

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 -9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001330348.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-101007870-A-AAAG is Benign according to our data. Variant chr2-101007870-A-AAAG is described in ClinVar as [Benign]. Clinvar id is 1248315.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D8	NM_001330348.2	c.3418_3419insCTT	p.Thr1139_Phe1140insSer	inframe_insertion	20/20	ENST00000409318.2
TBC1D8	NM_001102426.3	c.3373_3374insCTT	p.Thr1124_Phe1125insSer	inframe_insertion	20/20
RPL31	NM_001098577.3	c.346+1800_346+1802dup		intron_variant
TBC1D8	NR_138475.2	n.3384_3385insCTT		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D8	ENST00000409318.2	c.3418_3419insCTT	p.Thr1139_Phe1140insSer	inframe_insertion	20/20	5	NM_001330348.2	A1

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8056 AN: 152056 Hom.: 709 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0138 AC: 3437 AN: 249220 Hom.: 287 AF XY: 0.0102 AC XY: 1382 AN XY: 135204

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.00985

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.00793

GnomAD4 exome AF: 0.00571 AC: 8345 AN: 1461690 Hom.: 655 Cov.: 29 AF XY: 0.00496 AC XY: 3605 AN XY: 727124

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0109

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000495

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0532 AC: 8090 AN: 152174 Hom.: 715 Cov.: 32 AF XY: 0.0521 AC XY: 3874 AN XY: 74424

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.0196

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.00908 Hom.: 69

Bravo AF: 0.0609

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00119

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

Jul 15, 2020

This variant is associated with the following publications: (PMID: 32098966) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs150740812; hg19: chr2-101624332;