Genetic Variant TBC1D7-LOC100130357:c.*39+10290G>A (chr6-13294772-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001318809.2(TBC1D7-LOC100130357):c.*39+10290G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,242,554 control chromosomes in the GnomAD database, including 23,802 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 0.17 ( 2245 hom., cov: 33)

Exomes 𝑓: 0.19 ( 21557 hom. )

Consequence

TBC1D7-LOC100130357
NM_001318809.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.32

Publications

9 publications found

Variant links:

Genes affected

TBC1D7-LOC100130357 (HGNC:):

TBC1D7-LOC100130357 links:

TBC1D7 (HGNC:21066): (TBC1 domain family member 7) This gene encodes a member of the TBC-domain containing protein family. The encoded protein functions as a subunit of the tuberous sclerosis TSC1-TSC2 complex which plays a role in the regulation of cellular growth and differentiation. Mutations in this gene have been associated with autosomal recessive megalencephaly. Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between this locus and downstream LOC100130357. [provided by RefSeq, Jan 2016]

TBC1D7 Gene-Disease associations (from GenCC):

macrocephaly/megalencephaly syndrome, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

TBC1D7 links:

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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=-0.94).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein
TBC1D7-LOC100130357	NM_001318809.2	c.*39+10290G>A	intron	N/A	NP_001305738.1
TBC1D7-LOC100130357	NR_134872.2	n.712+24G>A	intron	N/A
LOC100130357	NR_160971.1	n.318+24G>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TBC1D7	ENST00000606214.5	TSL:5	c.*39+10290G>A	intron	N/A	ENSP00000475727.1	Q9P0N9-1
TBC1D7	ENST00000906917.1		c.*40-7664G>A	intron	N/A	ENSP00000576976.1
TBC1D7	ENST00000421203.6	TSL:2	n.*82+24G>A	intron	N/A	ENSP00000401438.2	B4DK47

Frequencies

GnomAD3 genomes

AF:

0.168

AC:

25491

AN:

152122

Hom.:

2250

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.155

Gnomad ASJ

AF:

0.183

Gnomad EAS

AF:

0.268

Gnomad SAS

AF:

0.307

Gnomad FIN

AF:

0.165

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.161

GnomAD2 exomes

AF:

0.200

AC:

27715

AN:

138912

AF XY:

0.208

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.270

Gnomad FIN exome

AF:

0.150

Gnomad NFE exome

AF:

0.188

Gnomad OTH exome

AF:

0.192

GnomAD4 exome

AF:

0.194

AC:

211373

AN:

1090312

Hom.:

21557

Cov.:

AF XY:

0.197

AC XY:

106075

AN XY:

537356

show subpopulations

African (AFR)

AF:

0.102

AC:

2381

AN:

23382

American (AMR)

AF:

0.153

AC:

4320

AN:

28186

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

2751

AN:

15624

East Asian (EAS)

AF:

0.267

AC:

3361

AN:

12576

South Asian (SAS)

AF:

0.292

AC:

22000

AN:

75230

European-Finnish (FIN)

AF:

0.153

AC:

2044

AN:

13338

Middle Eastern (MID)

AF:

0.197

AC:

851

AN:

4326

European-Non Finnish (NFE)

AF:

0.189

AC:

165777

AN:

877544

Other (OTH)

AF:

0.197

AC:

7888

AN:

40106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

8023

16045

24068

32090

40113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6762

13524

20286

27048

33810

<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:

0.167

AC:

25491

AN:

152242

Hom.:

2245

Cov.:

AF XY:

0.169

AC XY:

12578

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.114

AC:

4721

AN:

41550

American (AMR)

AF:

0.155

AC:

2371

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

635

AN:

3472

East Asian (EAS)

AF:

0.268

AC:

1386

AN:

5178

South Asian (SAS)

AF:

0.307

AC:

1478

AN:

4818

European-Finnish (FIN)

AF:

0.165

AC:

1747

AN:

10598

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12618

AN:

68002

Other (OTH)

AF:

0.161

AC:

340

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1122

2243

3365

4486

5608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.173

Hom.:

508

Bravo

AF:

0.160

Asia WGS

AF:

0.289

AC:

1003

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.49

(source)

DANN

Benign

0.72

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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