rs10101626

Variant names:

• chr8-123142457-G-T
• rs10101626
• NM_145647.4:c.2835+1G>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PVS1_Moderate PP3 BA1

The NM_145647.4(TBC1D31):​c.2835+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.189 in 1,534,894 control chromosomes in the GnomAD database, including 28,132 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3251 hom., cov: 31)
  • Exomes 𝑓: 0.19 (24881 hom.)
• Consequence: TBC1D31 NM_145647.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.60

Genes affected

TBC1D31 (HGNC:30888): (TBC1 domain family member 31) Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06091846 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, MutationTaster was below the threshold]
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D31	NM_145647.4	c.2835+1G>T		splice_donor_variant, intron_variant	Intron 19 of 21	ENST00000287380.6	NP_663622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D31	ENST00000287380.6	c.2835+1G>T		splice_donor_variant, intron_variant	Intron 19 of 21	1	NM_145647.4	ENSP00000287380.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 30898 AN: 150920 Hom.: 3244 Cov.: 31

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.193 AC: 36583 AN: 189302 Hom.: 3541 AF XY: 0.194 AC XY: 20196 AN XY: 103880

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.188 AC: 259618 AN: 1383864 Hom.: 24881 Cov.: 29 AF XY: 0.188 AC XY: 129011 AN XY: 685516

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.184

Gnomad4 OTH exome AF: 0.194

GnomAD4 genome AF: 0.205 AC: 30922 AN: 151030 Hom.: 3251 Cov.: 31 AF XY: 0.204 AC XY: 15025 AN XY: 73778

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.221

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.190

Alfa AF: 0.195 Hom.: 7006

Bravo AF: 0.208

TwinsUK AF: 0.201 AC: 746

ALSPAC AF: 0.191 AC: 736

ExAC AF: 0.195 AC: 23628

Asia WGS AF: 0.217 AC: 752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs10101626; hg19: chr8-124154697; COSMIC: COSV54870185; COSMIC: COSV54870185;