rs35859249

Variant names:

• chr4-37902468-C-T
• rs35859249
• NM_001396959.1:c.373C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-37902468-C-T
• chr4-37902468-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001396959.1(TBC1D1):​c.373C>T​(p.Arg125Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0922 in 1,612,780 control chromosomes in the GnomAD database, including 7,332 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.079 (590 hom., cov: 32)
  • Exomes 𝑓: 0.094 (6742 hom.)
• Consequence: TBC1D1 NM_001396959.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.45
• Publications: 50 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):

• non-syndromic renal or urinary tract malformation

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016258061).
• BP6: Variant 4-37902468-C-T is Benign according to our data. Variant chr4-37902468-C-T is described in ClinVar as Benign. ClinVar VariationId is 3058918.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001396959.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D1	NM_001396959.1	MANE Select	c.373C>T	p.Arg125Trp	missense	Exon 2 of 22	NP_001383888.1	A0A8V8TNS9
	TBC1D1	NM_015173.4		c.373C>T	p.Arg125Trp	missense	Exon 2 of 20	NP_055988.2
	TBC1D1	NM_001253912.2		c.373C>T	p.Arg125Trp	missense	Exon 2 of 21	NP_001240841.1	Q86TI0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D1	ENST00000698857.1	MANE Select	c.373C>T	p.Arg125Trp	missense	Exon 2 of 22	ENSP00000513987.1	A0A8V8TNS9
	TBC1D1	ENST00000261439.9	TSL:1	c.373C>T	p.Arg125Trp	missense	Exon 2 of 20	ENSP00000261439.4	Q86TI0-1
	TBC1D1	ENST00000961338.1		c.373C>T	p.Arg125Trp	missense	Exon 2 of 23	ENSP00000631397.1

Frequencies

GnomAD3 genomes AF: 0.0792 AC: 12038 AN: 151964 Hom.: 592 Cov.: 32

Gnomad AFR AF: 0.0292

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0694

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0898

Gnomad OTH AF: 0.0939

GnomAD2 exomes AF: 0.0972 AC: 24354 AN: 250464 AF XY: 0.0997

Gnomad AFR exome AF: 0.0267

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.123

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.0904

Gnomad OTH exome AF: 0.0910

GnomAD4 exome AF: 0.0936 AC: 136736 AN: 1460698 Hom.: 6742 Cov.: 34 AF XY: 0.0945 AC XY: 68670 AN XY: 726650

African (AFR) AF: 0.0263 AC: 880 AN: 33472

American (AMR) AF: 0.0770 AC: 3439 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3631 AN: 26056

East Asian (EAS) AF: 0.104 AC: 4140 AN: 39698

South Asian (SAS) AF: 0.123 AC: 10581 AN: 86118

European-Finnish (FIN) AF: 0.132 AC: 7057 AN: 53338

Middle Eastern (MID) AF: 0.0763 AC: 440 AN: 5766

European-Non Finnish (NFE) AF: 0.0907 AC: 100842 AN: 1111246

Other (OTH) AF: 0.0949 AC: 5726 AN: 60336

GnomAD4 genome AF: 0.0791 AC: 12029 AN: 152082 Hom.: 590 Cov.: 32 AF XY: 0.0822 AC XY: 6111 AN XY: 74310

African (AFR) AF: 0.0291 AC: 1207 AN: 41516

American (AMR) AF: 0.0694 AC: 1061 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3468

East Asian (EAS) AF: 0.116 AC: 597 AN: 5160

South Asian (SAS) AF: 0.131 AC: 630 AN: 4822

European-Finnish (FIN) AF: 0.151 AC: 1594 AN: 10538

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0898 AC: 6102 AN: 67982

Other (OTH) AF: 0.0929 AC: 196 AN: 2110

Alfa AF: 0.0879 Hom.: 2620

Bravo AF: 0.0719

TwinsUK AF: 0.0895 AC: 332

ALSPAC AF: 0.0802 AC: 309

ESP6500AA AF: 0.0295 AC: 130

ESP6500EA AF: 0.0966 AC: 831

ExAC AF: 0.0939 AC: 11394

Asia WGS AF: 0.109 AC: 379 AN: 3478

EpiCase AF: 0.0908

EpiControl AF: 0.0940

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TBC1D1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.017	D
Polyphen		0.96	D
Vest4		0.21
MPC		1.0
ClinPred		0.019	T
GERP RS		3.1
Varity_R		0.059
gMVP		0.31
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35859249; hg19: chr4-37904089; COSMIC: COSV54718640;