chr4-38014774-T-G

Variant names:

• chr4-38014774-T-G
• rs10501
• NM_001396959.1:c.683T>G

Variant summary

Our verdict is Benign. The variant received -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. 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: 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
• Publications: 26 publications found

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]

TBC1D1 Gene-Disease associations (from GenCC):

• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TBC1D1	NM_001396959.1	c.683T>G	p.Val228Gly	missense_variant	Exon 3 of 22	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D1	ENST00000698857.1	c.683T>G	p.Val228Gly	missense_variant	Exon 3 of 22		NM_001396959.1	ENSP00000513987.1

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

GnomAD2 exomes AF: 0.477 AC: 115185 AN: 241332 AF XY: 0.474

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 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

African (AFR) AF: 0.652 AC: 21251 AN: 32616

American (AMR) AF: 0.496 AC: 21310 AN: 43006

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 12513 AN: 24222

East Asian (EAS) AF: 0.736 AC: 28132 AN: 38224

South Asian (SAS) AF: 0.513 AC: 44007 AN: 85744

European-Finnish (FIN) AF: 0.475 AC: 22167 AN: 46646

Middle Eastern (MID) AF: 0.488 AC: 2648 AN: 5430

European-Non Finnish (NFE) AF: 0.429 AC: 459007 AN: 1070568

Other (OTH) AF: 0.494 AC: 27996 AN: 56724

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

African (AFR) AF: 0.628 AC: 25850 AN: 41176

American (AMR) AF: 0.471 AC: 7098 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1713 AN: 3428

East Asian (EAS) AF: 0.710 AC: 3563 AN: 5016

South Asian (SAS) AF: 0.539 AC: 2493 AN: 4626

European-Finnish (FIN) AF: 0.466 AC: 4660 AN: 9996

Middle Eastern (MID) AF: 0.451 AC: 130 AN: 288

European-Non Finnish (NFE) AF: 0.422 AC: 28257 AN: 66908

Other (OTH) AF: 0.487 AC: 1020 AN: 2094

Alfa AF: 0.452 Hom.: 8909

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;.
PhyloP100		1.4
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10501; hg19: chr4-38016395; COSMIC: COSV54714821; COSMIC: COSV54714821;