4-38014774-T-G

Position:

• chr4-38014774-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001396959.1(TBC1D1):​c.683T>G​(p.Val228Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 1,552,666 control chromosomes in the GnomAD database, including 163,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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: 𝑓 0.50 (19411 hom., cov: 30)
  • Exomes 𝑓: 0.46 (143603 hom.)
• 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.5685264E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D1	NM_001396959.1	c.683T>G	p.Val228Gly	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>G	p.Val228Gly	missense_variant	3/22		NM_001396959.1	ENSP00000513987	A2

Frequencies

GnomAD3 genomes AF: 0.502 AC: 75047 AN: 149362 Hom.: 19368 Cov.: 30

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.484

GnomAD3 exomes AF: 0.477 AC: 115185 AN: 241332 Hom.: 28562 AF XY: 0.474 AC XY: 62735 AN XY: 132322

Gnomad AFR exome AF: 0.634

Gnomad AMR exome AF: 0.478

Gnomad ASJ exome AF: 0.486

Gnomad EAS exome AF: 0.685

Gnomad SAS exome AF: 0.523

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.455 AC: 639031 AN: 1403180 Hom.: 143603 Cov.: 54 AF XY: 0.457 AC XY: 318554 AN XY: 696982

Gnomad4 AFR exome AF: 0.652

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.517

Gnomad4 EAS exome AF: 0.736

Gnomad4 SAS exome AF: 0.513

Gnomad4 FIN exome AF: 0.475

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.494

GnomAD4 genome AF: 0.503 AC: 75146 AN: 149486 Hom.: 19411 Cov.: 30 AF XY: 0.504 AC XY: 36785 AN XY: 72956

Gnomad4 AFR AF: 0.628

Gnomad4 AMR AF: 0.471

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.710

Gnomad4 SAS AF: 0.539

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.487

Alfa AF: 0.436 Hom.: 5739

Bravo AF: 0.507

TwinsUK AF: 0.412 AC: 1528

ALSPAC AF: 0.407 AC: 1570

ESP6500AA AF: 0.589 AC: 2525

ESP6500EA AF: 0.418 AC: 3573

ExAC AF: 0.472 AC: 56930

Asia WGS AF: 0.631 AC: 2194 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.9
DANN	Benign	0.22
DEOGEN2	Benign	0.018	.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.021	T;T;T
MetaRNN	Benign	0.0000036	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.062
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.030
MPC		0.69
ClinPred		0.0019	T
GERP RS		0.31
Varity_R		0.020
gMVP		0.33

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; COSMIC: COSV54714821; COSMIC: COSV54714821;