Genetic Variant TBC1D31:p.Ala85Pro (chr8-123082730-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145647.4(TBC1D31):c.253G>C(p.Ala85Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A85T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TBC1D31
NM_145647.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.42

Publications

0 publications found

Variant links:

Genes affected

TBC1D31 (HGNC:30888): (TBC1 domain family member 31) Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

TBC1D31 Gene-Disease associations (from GenCC):

congenital anomaly of kidney and urinary tract
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

TBC1D31 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145647.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D31	NM_145647.4	MANE Select	c.253G>C	p.Ala85Pro	missense	Exon 3 of 22	NP_663622.2	Q96DN5-1
TBC1D31	NM_001363149.1		c.223G>C	p.Ala75Pro	missense	Exon 3 of 22	NP_001350078.1
TBC1D31	NM_001363150.1		c.253G>C	p.Ala85Pro	missense	Exon 3 of 21	NP_001350079.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBC1D31	ENST00000287380.6	TSL:1 MANE Select	c.253G>C	p.Ala85Pro	missense	Exon 3 of 22	ENSP00000287380.1	Q96DN5-1
TBC1D31	ENST00000327098.9	TSL:1	c.253G>C	p.Ala85Pro	missense	Exon 3 of 20	ENSP00000312701.5	Q96DN5-3
TBC1D31	ENST00000522420.5	TSL:1	c.26-1432G>C		intron	N/A	ENSP00000429334.1	E7ERK7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250346

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460370

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726592

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:

33466

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111894

Other (OTH)

AF:

0.00

AC:

AN:

60382

⚠️ 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: 0.325

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0044

Eigen

Benign

0.087

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.2

PhyloP100

7.4

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.64

REVEL

Benign

0.24

Sift

Benign

0.28

Sift4G

Benign

0.20

Polyphen

0.17

Vest4

0.44

MutPred

0.60

Gain of relative solvent accessibility (P = 0.09)

MVP

0.74

MPC

0.098

ClinPred

0.56

GERP RS

4.8

Varity_R

0.24

gMVP

0.62

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over