chr4-38014774-T-C

Position:

• chr4-38014774-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001396959.1(TBC1D1):​c.683T>C​(p.Val228Ala) 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: 30)
• Consequence: TBC1D1 NM_001396959.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043564767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D1	NM_001396959.1	c.683T>C	p.Val228Ala	missense_variant	3/22	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D1	ENST00000698857.1	c.683T>C	p.Val228Ala	missense_variant	3/22		NM_001396959.1	ENSP00000513987	A2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.2
DANN	Benign	0.31
DEOGEN2	Benign	0.020	.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.059	T;T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.044	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.36	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.77	T;T;T
Sift4G	Benign	0.75	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.029
MutPred		0.11		Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);.;
MVP		0.15
MPC		0.63
ClinPred		0.018	T
GERP RS		0.31
Varity_R		0.015
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs10501; hg19: chr4-38016395;