rs2279027

Positions:

• chr4-37902135-T-A
• chr4-37902135-T-C
• chr4-37902135-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001396959.1(TBC1D1):​c.40T>A​(p.Ser14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: TBC1D1 NM_001396959.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.247

Genes affected

TBC1D1 (HGNC:11578): (TBC1 domain family member 1) TBC1D1 is the founding member of a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and differentiation. These proteins share significant homology with TRE2 (USP6; MIM 604334), yeast Bub2, and CDC16 (MIM 603461) (White et al., 2000 [PubMed 10965142]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087320656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D1	NM_001396959.1	c.40T>A	p.Ser14Thr	missense_variant	2/22	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D1	ENST00000698857.1	c.40T>A	p.Ser14Thr	missense_variant	2/22		NM_001396959.1	ENSP00000513987	A2
TBC1D1	ENST00000261439.9	c.40T>A	p.Ser14Thr	missense_variant	2/20	1		ENSP00000261439	P2
TBC1D1	ENST00000508802.5	c.40T>A	p.Ser14Thr	missense_variant	2/21	2		ENSP00000423651
TBC1D1	ENST00000402522.1	c.40T>A	p.Ser14Thr	missense_variant	2/3	2		ENSP00000383994

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.027	.;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.050	N;N;N
REVEL	Benign	0.074
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.24	T;T;T
Polyphen		0.039	.;B;.
Vest4		0.11
MutPred		0.38		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP		0.22
MPC		0.49
ClinPred		0.41	T
GERP RS		4.9
Varity_R		0.042
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2279027; hg19: chr4-37903756;