4-38137235-G-A

Variant names:

• chr4-38137235-G-A
• rs13110318
• NM_001396959.1:c.3689G>A

Variant summary

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

The NM_001396959.1(TBC1D1):​c.3689G>A​(p.Arg1230Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0927 in 1,612,330 control chromosomes in the GnomAD database, including 7,434 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1230W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.087 (669 hom., cov: 32)
  • Exomes 𝑓: 0.093 (6765 hom.)
• Consequence: TBC1D1 NM_001396959.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• Publications: 32 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=0.0014815629).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.141 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.3689G>A	p.Arg1230Gln	missense	Exon 22 of 22	NP_001383888.1
	TBC1D1	NM_015173.4		c.3407G>A	p.Arg1136Gln	missense	Exon 20 of 20	NP_055988.2
	TBC1D1	NM_001253912.2		c.3380G>A	p.Arg1127Gln	missense	Exon 21 of 21	NP_001240841.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D1	ENST00000698857.1	MANE Select	c.3689G>A	p.Arg1230Gln	missense	Exon 22 of 22	ENSP00000513987.1
	TBC1D1	ENST00000261439.9	TSL:1	c.3407G>A	p.Arg1136Gln	missense	Exon 20 of 20	ENSP00000261439.4
	TBC1D1	ENST00000961338.1		c.3728G>A	p.Arg1243Gln	missense	Exon 23 of 23	ENSP00000631397.1

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 13239 AN: 152096 Hom.: 666 Cov.: 32

Gnomad AFR AF: 0.0511

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0986

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.0497

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0893

Gnomad OTH AF: 0.0974

GnomAD2 exomes AF: 0.104 AC: 25956 AN: 250600 AF XY: 0.0983

Gnomad AFR exome AF: 0.0503

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.0916

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.0932 AC: 136151 AN: 1460116 Hom.: 6765 Cov.: 32 AF XY: 0.0915 AC XY: 66459 AN XY: 726352

African (AFR) AF: 0.0504 AC: 1685 AN: 33432

American (AMR) AF: 0.187 AC: 8349 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2634 AN: 26136

East Asian (EAS) AF: 0.117 AC: 4638 AN: 39700

South Asian (SAS) AF: 0.0522 AC: 4502 AN: 86176

European-Finnish (FIN) AF: 0.119 AC: 6324 AN: 53296

Middle Eastern (MID) AF: 0.103 AC: 458 AN: 4428

European-Non Finnish (NFE) AF: 0.0917 AC: 101963 AN: 1111974

Other (OTH) AF: 0.0929 AC: 5598 AN: 60250

GnomAD4 genome AF: 0.0870 AC: 13250 AN: 152214 Hom.: 669 Cov.: 32 AF XY: 0.0885 AC XY: 6588 AN XY: 74422

African (AFR) AF: 0.0511 AC: 2123 AN: 41548

American (AMR) AF: 0.146 AC: 2227 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0986 AC: 342 AN: 3470

East Asian (EAS) AF: 0.114 AC: 590 AN: 5162

South Asian (SAS) AF: 0.0498 AC: 240 AN: 4822

European-Finnish (FIN) AF: 0.119 AC: 1262 AN: 10590

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0893 AC: 6071 AN: 68010

Other (OTH) AF: 0.0959 AC: 203 AN: 2116

Alfa AF: 0.0898 Hom.: 1730

Bravo AF: 0.0910

TwinsUK AF: 0.0963 AC: 357

ALSPAC AF: 0.0874 AC: 337

ESP6500AA AF: 0.0536 AC: 236

ESP6500EA AF: 0.0919 AC: 790

ExAC AF: 0.0974 AC: 11828

Asia WGS AF: 0.0820 AC: 286 AN: 3478

EpiCase AF: 0.0922

EpiControl AF: 0.0952

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.0064
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.098
Sift	Benign	0.30	T
Sift4G	Benign	0.23	T
Polyphen		0.45	P
Vest4		0.40
MPC		0.58
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.16
gMVP		0.35
Mutation Taster		=93/7	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: rs13110318; hg19: chr4-38138856; COSMIC: COSV54724540;