4-38053116-C-T

Variant names:

• chr4-38053116-C-T
• rs58983546
• NM_001396959.1:c.2083C>T
• TBC1D1 p.Arg695Cys

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001396959.1(TBC1D1):​c.2083C>T​(p.Arg695Cys) variant causes a missense change. The variant allele was found at a frequency of 0.118 in 1,496,364 control chromosomes in the GnomAD database, including 11,612 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (970 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10642 hom.)
• Consequence: TBC1D1 NM_001396959.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016778111).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 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.2083C>T	p.Arg695Cys	missense	Exon 13 of 22	NP_001383888.1	A0A8V8TNS9
	TBC1D1	NM_001253912.2		c.2083C>T	p.Arg695Cys	missense	Exon 13 of 21	NP_001240841.1	Q86TI0-2
	TBC1D1	NM_015173.4		c.1911-1083C>T		intron	N/A	NP_055988.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D1	ENST00000698857.1	MANE Select	c.2083C>T	p.Arg695Cys	missense	Exon 13 of 22	ENSP00000513987.1	A0A8V8TNS9
	TBC1D1	ENST00000261439.9	TSL:1	c.1911-1083C>T		intron	N/A	ENSP00000261439.4	Q86TI0-1
	TBC1D1	ENST00000961338.1		c.2083C>T	p.Arg695Cys	missense	Exon 13 of 23	ENSP00000631397.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15511 AN: 151920 Hom.: 970 Cov.: 32

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.0891

Gnomad ASJ AF: 0.0960

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.101 AC: 11516 AN: 114018 AF XY: 0.0985

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.0627

Gnomad ASJ exome AF: 0.0874

Gnomad EAS exome AF: 0.000266

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.120 AC: 160816 AN: 1344326 Hom.: 10642 Cov.: 30 AF XY: 0.118 AC XY: 78137 AN XY: 661890

African (AFR) AF: 0.0522 AC: 1498 AN: 28694

American (AMR) AF: 0.0708 AC: 1842 AN: 26008

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 2146 AN: 23650

East Asian (EAS) AF: 0.000331 AC: 11 AN: 33198

South Asian (SAS) AF: 0.0333 AC: 2302 AN: 69026

European-Finnish (FIN) AF: 0.178 AC: 8391 AN: 47090

Middle Eastern (MID) AF: 0.111 AC: 609 AN: 5500

European-Non Finnish (NFE) AF: 0.131 AC: 138199 AN: 1055702

Other (OTH) AF: 0.105 AC: 5818 AN: 55458

GnomAD4 genome AF: 0.102 AC: 15510 AN: 152038 Hom.: 970 Cov.: 32 AF XY: 0.101 AC XY: 7501 AN XY: 74292

African (AFR) AF: 0.0550 AC: 2281 AN: 41494

American (AMR) AF: 0.0889 AC: 1359 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0960 AC: 333 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4822

European-Finnish (FIN) AF: 0.173 AC: 1816 AN: 10510

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9149 AN: 67968

Other (OTH) AF: 0.112 AC: 236 AN: 2114

Alfa AF: 0.0945 Hom.: 504

Bravo AF: 0.0929

Asia WGS AF: 0.0220 AC: 76 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.2	T
PhyloP100		6.1
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.21
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.045	D
Mutation Taster		=90/10	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs58983546;

hg19: chr4-38054737;

COSMIC: COSV54728289;

COSMIC: COSV54728289;