rs144176745

Variant names:

• chr16-30358146-C-A
• rs144176745
• NM_015527.4:c.2225G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-30358146-C-A
• chr16-30358146-C-G
• chr16-30358146-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015527.4(TBC1D10B):​c.2225G>T​(p.Arg742Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,549,474 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R742Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (4 hom.)
• Consequence: TBC1D10B NM_015527.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.723

Genes affected

TBC1D10B (HGNC:24510): (TBC1 domain family member 10B) Small G proteins of the RAB family (see MIM 179508) function in intracellular vesicle trafficking by switching from the GTP-bound state to the GDP-bound state with the assistance of guanine nucleotide exchange factors (GEFs; see MIM 609700) and GTPase-activating proteins (GAPs). TBC1D10B functions as a GAP for several proteins of the Rab family (Ishibashi et al., 2009 [PubMed 19077034]).[supplied by OMIM, Nov 2010]

CD2BP2-DT (HGNC:53029): (CD2BP2 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004202485).
• BS2: High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D10B	NM_015527.4	c.2225G>T	p.Arg742Leu	missense_variant	Exon 9 of 9	ENST00000409939.8	NP_056342.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D10B	ENST00000409939.8	c.2225G>T	p.Arg742Leu	missense_variant	Exon 9 of 9	1	NM_015527.4	ENSP00000386538.3

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 151776 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00130 AC: 205 AN: 157954 AF XY: 0.00120

Gnomad AFR exome AF: 0.000777

Gnomad AMR exome AF: 0.000686

Gnomad ASJ exome AF: 0.000234

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000769

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00246 AC: 3445 AN: 1397580 Hom.: 4 Cov.: 31 AF XY: 0.00236 AC XY: 1628 AN XY: 689238

African (AFR) AF: 0.000317 AC: 10 AN: 31560

American (AMR) AF: 0.000813 AC: 29 AN: 35652

Ashkenazi Jewish (ASJ) AF: 0.000199 AC: 5 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35630

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 79006

European-Finnish (FIN) AF: 0.000748 AC: 37 AN: 49464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00302 AC: 3258 AN: 1077364

Other (OTH) AF: 0.00181 AC: 105 AN: 58044

GnomAD4 genome AF: 0.00139 AC: 211 AN: 151894 Hom.: 0 Cov.: 33 AF XY: 0.00110 AC XY: 82 AN XY: 74282

African (AFR) AF: 0.000676 AC: 28 AN: 41402

American (AMR) AF: 0.00131 AC: 20 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 67892

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00239 Hom.: 0

Bravo AF: 0.00138

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00123 AC: 5

ESP6500EA AF: 0.00262 AC: 21

ExAC AF: 0.000504 AC: 36

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2225G>T (p.R742L) alteration is located in exon 9 (coding exon 9) of the TBC1D10B gene. This alteration results from a G to T substitution at nucleotide position 2225, causing the arginine (R) at amino acid position 742 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.052	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.72
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.091
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.21	T
Polyphen		0.023	B
Vest4		0.24
MVP		0.13
MPC		0.15
ClinPred		0.017	T
GERP RS		2.2
Varity_R		0.11
gMVP		0.081
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

Publications

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Other links and lift over

dbSNP: rs144176745; hg19: chr16-30369467; COSMIC: COSV59769707; COSMIC: COSV59769707;