rs2303422

Variant names:

• chr4-38090179-A-G
• rs2303422
• NM_001396959.1:c.2518+62A>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.2518+62A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,502,552 control chromosomes in the GnomAD database, including 21,720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1823 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19897 hom.)
• Consequence: TBC1D1 NM_001396959.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.173
• Publications: 9 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 (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.403 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.2518+62A>G		intron	N/A	NP_001383888.1	A0A8V8TNS9
	TBC1D1	NM_015173.4		c.2236+62A>G		intron	N/A	NP_055988.2
	TBC1D1	NM_001253912.2		c.2518+62A>G		intron	N/A	NP_001240841.1	Q86TI0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D1	ENST00000698857.1	MANE Select	c.2518+62A>G		intron	N/A	ENSP00000513987.1	A0A8V8TNS9
	TBC1D1	ENST00000261439.9	TSL:1	c.2236+62A>G		intron	N/A	ENSP00000261439.4	Q86TI0-1
	TBC1D1	ENST00000961338.1		c.2557+62A>G		intron	N/A	ENSP00000631397.1

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19916 AN: 152202 Hom.: 1821 Cov.: 33

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.136

GnomAD4 exome AF: 0.161 AC: 217004 AN: 1350232 Hom.: 19897 AF XY: 0.162 AC XY: 109725 AN XY: 677442

African (AFR) AF: 0.0232 AC: 699 AN: 30166

American (AMR) AF: 0.200 AC: 7906 AN: 39488

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 5109 AN: 25150

East Asian (EAS) AF: 0.419 AC: 16388 AN: 39106

South Asian (SAS) AF: 0.214 AC: 17388 AN: 81172

European-Finnish (FIN) AF: 0.124 AC: 6600 AN: 53182

Middle Eastern (MID) AF: 0.114 AC: 599 AN: 5264

European-Non Finnish (NFE) AF: 0.150 AC: 152904 AN: 1020164

Other (OTH) AF: 0.166 AC: 9411 AN: 56540

GnomAD4 genome AF: 0.131 AC: 19926 AN: 152320 Hom.: 1823 Cov.: 33 AF XY: 0.132 AC XY: 9813 AN XY: 74486

African (AFR) AF: 0.0285 AC: 1187 AN: 41586

American (AMR) AF: 0.171 AC: 2619 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 721 AN: 3472

East Asian (EAS) AF: 0.418 AC: 2166 AN: 5184

South Asian (SAS) AF: 0.219 AC: 1058 AN: 4834

European-Finnish (FIN) AF: 0.134 AC: 1423 AN: 10602

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10369 AN: 68014

Other (OTH) AF: 0.138 AC: 292 AN: 2114

Alfa AF: 0.134 Hom.: 344

Bravo AF: 0.132

Asia WGS AF: 0.309 AC: 1074 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.9
DANN	Benign	0.69
PhyloP100		0.17
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

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

Other links and lift over

dbSNP: rs2303422;

hg19: chr4-38091800;

COSMIC: COSV54715381;

COSMIC: COSV54715381;