Genetic Variant TBC1D1:c.1629+21A>G (chr4-38045924-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001396959.1(TBC1D1):c.1629+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,603,316 control chromosomes in the GnomAD database, including 80,386 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 0.32 ( 8224 hom., cov: 32)

Exomes 𝑓: 0.31 ( 72162 hom. )

Consequence

TBC1D1
NM_001396959.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.498

Publications

12 publications found

Variant links:

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

TBC1D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TBC1D1	NM_001396959.1	MANE Select	c.1629+21A>G	intron	N/A	NP_001383888.1	A0A8V8TNS9
TBC1D1	NM_015173.4		c.1629+21A>G	intron	N/A	NP_055988.2
TBC1D1	NM_001253912.2		c.1629+21A>G	intron	N/A	NP_001240841.1	Q86TI0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TBC1D1	ENST00000698857.1	MANE Select	c.1629+21A>G	intron	N/A	ENSP00000513987.1	A0A8V8TNS9
TBC1D1	ENST00000261439.9	TSL:1	c.1629+21A>G	intron	N/A	ENSP00000261439.4	Q86TI0-1
TBC1D1	ENST00000961338.1		c.1629+21A>G	intron	N/A	ENSP00000631397.1

Frequencies

GnomAD3 genomes

AF:

0.320

AC:

48648

AN:

151854

Hom.:

8217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.355

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.293

Gnomad ASJ

AF:

0.354

Gnomad EAS

AF:

0.620

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.258

Gnomad NFE

AF:

0.292

Gnomad OTH

AF:

0.302

GnomAD2 exomes

AF:

0.327

AC:

82140

AN:

251080

AF XY:

0.326

show subpopulations

Gnomad AFR exome

AF:

0.356

Gnomad AMR exome

AF:

0.299

Gnomad ASJ exome

AF:

0.340

Gnomad EAS exome

AF:

0.614

Gnomad FIN exome

AF:

0.239

Gnomad NFE exome

AF:

0.292

Gnomad OTH exome

AF:

0.309

GnomAD4 exome

AF:

0.307

AC:

446250

AN:

1451344

Hom.:

72162

Cov.:

AF XY:

0.308

AC XY:

222423

AN XY:

722754

show subpopulations

African (AFR)

AF:

0.350

AC:

11634

AN:

33268

American (AMR)

AF:

0.298

AC:

13343

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

8933

AN:

26054

East Asian (EAS)

AF:

0.654

AC:

25919

AN:

39650

South Asian (SAS)

AF:

0.357

AC:

30681

AN:

86016

European-Finnish (FIN)

AF:

0.237

AC:

12629

AN:

53264

Middle Eastern (MID)

AF:

0.292

AC:

1678

AN:

5754

European-Non Finnish (NFE)

AF:

0.292

AC:

321955

AN:

1102602

Other (OTH)

AF:

0.324

AC:

19478

AN:

60032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

15294

30588

45881

61175

76469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10836

21672

32508

43344

54180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.320

AC:

48685

AN:

151972

Hom.:

8224

Cov.:

AF XY:

0.317

AC XY:

23543

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.355

AC:

14704

AN:

41432

American (AMR)

AF:

0.293

AC:

4475

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

1227

AN:

3466

East Asian (EAS)

AF:

0.620

AC:

3204

AN:

5164

South Asian (SAS)

AF:

0.363

AC:

1747

AN:

4818

European-Finnish (FIN)

AF:

0.243

AC:

2562

AN:

10538

Middle Eastern (MID)

AF:

0.257

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.293

AC:

19880

AN:

67962

Other (OTH)

AF:

0.304

AC:

641

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1674

3347

5021

6694

8368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

498

996

1494

1992

2490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.309

Hom.:

7257

Bravo

AF:

0.329

Asia WGS

AF:

0.486

AC:

1690

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.58

(source)

DANN

Benign

0.75

PhyloP100

-0.50

PromoterAI

0.0020

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over