Genetic Variant TBC1D3B:p.Ile149Val (chr17-36171907-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001001417.7(TBC1D3B):c.445A>G(p.Ile149Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 149,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000064 ( 6 hom. )

Failed GnomAD Quality Control

Consequence

TBC1D3B
NM_001001417.7 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.150

Variant links:

Genes affected

TBC1D3B (HGNC:27011): (TBC1 domain family member 3B) This gene encodes a protein that is similar to TBC1 domain family, member 3. This protein contains a TBC (Tre-2, Bub2p, and Cdc16p) domain, which is found in proteins involved in RAB GTPase signaling and vesicle trafficking. There are multiple copies of this gene located within a cluster of chemokine genes on chromosome 17q. [provided by RefSeq, Apr 2009]

TBC1D3B links:

ENSG00000276241 (HGNC:):

ENSG00000276241 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.051583827).

BP6

Variant 17-36171907-T-C is Benign according to our data. Variant chr17-36171907-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2345611.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D3B	NM_001001417.7 link	c.445A>G	p.Ile149Val	missense_variant	Exon 7 of 14	ENST00000611257.5	NP_001001417.6	A6NDS4
TBC1D3B	XM_005257980.5 link	c.628A>G	p.Ile210Val	missense_variant	Exon 7 of 14		XP_005258037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBC1D3B	ENST00000611257.5 link	c.445A>G	p.Ile149Val	missense_variant	Exon 7 of 14	1	NM_001001417.7	ENSP00000478473.1	A6NDS4
TBC1D3B	ENST00000622280.1 link	n.417A>G		non_coding_transcript_exon_variant	Exon 2 of 4	5
ENSG00000276241	ENST00000617914.1 link	n.158-5288T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

149176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000469

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000756

Gnomad OTH

AF:

0.00246

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000640

AC:

AN:

1453672

Hom.:

Cov.:

AF XY:

0.0000802

AC XY:

AN XY:

723392

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000679

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000134

AC:

AN:

149292

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

72906

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000468

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000756

Gnomad4 OTH

AF:

0.00243

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 05, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.017

DANN

Benign

0.17

DEOGEN2

Benign

0.015

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.31

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.36

PrimateAI

Uncertain

0.71

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.082

MutPred

0.39

Loss of disorder (P = 0.2077);

MVP

0.043

ClinPred

0.039

Varity_R

0.054

gMVP

0.021

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over