dbSNP rs193920937: TMEM230:p.Val51Ala (chr20-5106258-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The ENST00000612323.4(TMEM230):c.152T>C(p.Val51Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMEM230
ENST00000612323.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 8.51

Publications

0 publications found

Variant links:

Genes affected

TMEM230 (HGNC:15876): (transmembrane protein 230) This gene encodes a multi-pass transmembrane protein that belongs to the TMEM134/TMEM230 protein family. The encoded protein localizes to secretory and recycling vesicle in the neuron and may be involved in synaptic vesicles trafficking and recycling. Mutations in this gene may be linked to familial Parkinson's disease. [provided by RefSeq, Mar 2017]

TMEM230 Gene-Disease associations (from GenCC):

Parkinson disease
Inheritance: SD, AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics

TMEM230 links:

Genome browser will be placed here

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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
TMEM230	NM_001330987.2 link	c.152T>C	p.Val51Ala	missense_variant	Exon 3 of 4	NP_001317916.1	A0A087WTT2
TMEM230	NM_001009924.2 link	c.152T>C	p.Val51Ala	missense_variant	Exon 4 of 5	NP_001009924.1	Q96A57-1
TMEM230	NM_001009925.2 link	c.152T>C	p.Val51Ala	missense_variant	Exon 3 of 4	NP_001009925.1	Q96A57-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM230	ENST00000202834.12 link	c.152T>C	p.Val51Ala	missense_variant	Exon 3 of 4	1		ENSP00000202834.7		Q96A57-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727220

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:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Prostate cancer

Uncertain:1

Science for Life laboratory, Karolinska Institutet

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.027

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

Eigen

Benign

-0.035

Eigen_PC

Benign

0.089

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

.;D;.;.;.;.;.;T;T;T

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.57

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

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

PhyloP100

8.5

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.21

Sift

Benign

0.37

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

Sift4G

Benign

0.18

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

Polyphen

0.0010, 0.045, 1.0

.;.;B;B;B;B;B;B;B;D

Vest4

0.59

MutPred

0.71

Loss of stability (P = 0.0254);Loss of stability (P = 0.0254);Loss of stability (P = 0.0254);Loss of stability (P = 0.0254);Loss of stability (P = 0.0254);Loss of stability (P = 0.0254);Loss of stability (P = 0.0254);.;Loss of stability (P = 0.0254);Loss of stability (P = 0.0254);

MVP

0.27

MPC

1.2

ClinPred

0.86

GERP RS

5.2

Varity_R

0.10

gMVP

0.79

Mutation Taster

=52/48

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over