dbSNP rs9381921: TBC1D7:p.Ala136Ser (chr6-13316684-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_016495.6(TBC1D7):c.406G>T(p.Ala136Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A136T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TBC1D7
NM_016495.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.34

Publications

0 publications found

Variant links:

Genes affected

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

TBC1D7 links:

TBC1D7-LOC100130357 (HGNC:):

TBC1D7-LOC100130357 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D7	NM_016495.6 link	c.406G>T	p.Ala136Ser	missense_variant	Exon 5 of 8	ENST00000379300.8	NP_057579.1	Q9P0N9-1A0A024QZX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D7	ENST00000379300.8 link	c.406G>T	p.Ala136Ser	missense_variant	Exon 5 of 8	1	NM_016495.6	ENSP00000368602.3		Q9P0N9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727200

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111946

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;T;T;.;T;.;.;.;.;.;.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;.;D;D;D;.;D;D;D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;L;.;.;.;.;.;.;.;.;.

PhyloP100

4.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.23

.;N;N;N;.;N;N;N;N;N;N;N

REVEL

Benign

0.072

Sift

Benign

0.18

.;T;T;T;.;T;T;T;T;T;T;T

Sift4G

Benign

0.68

T;T;T;T;T;T;T;.;T;.;.;T

Polyphen

0.12

B;B;B;B;.;.;.;.;P;.;.;.

Vest4

0.21

MutPred

0.36

Gain of disorder (P = 0.0505);Gain of disorder (P = 0.0505);Gain of disorder (P = 0.0505);.;.;.;.;Gain of disorder (P = 0.0505);.;.;Gain of disorder (P = 0.0505);Gain of disorder (P = 0.0505);

MVP

0.17

MPC

0.43

ClinPred

0.70

GERP RS

5.9

Varity_R

0.15

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.61

Position offset: -7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over