rs606231455

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP3_ModeratePP5BS2

The NM_001114748.2(TMEM240):c.511C>T(p.Arg171Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000904 in 1,549,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

TMEM240
NM_001114748.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 1.59

Publications

3 publications found

Variant links:

Genes affected

TMEM240 (HGNC:25186): (transmembrane protein 240) This gene encodes a transmembrane-domain containing protein found in the brain and cerebellum. Mutations in this gene result in spinocerebellar ataxia 21. [provided by RefSeq, Dec 2014]

TMEM240 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 21
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

TMEM240 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.881

PP5

Variant 1-1535370-G-A is Pathogenic according to our data. Variant chr1-1535370-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161196.

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM240	NM_001114748.2 link	c.511C>T	p.Arg171Trp	missense_variant	Exon 4 of 4	ENST00000378733.9	NP_001108220.1	Q5SV17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM240	ENST00000378733.9 link	c.511C>T	p.Arg171Trp	missense_variant	Exon 4 of 4	2	NM_001114748.2	ENSP00000368007.4		Q5SV17

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000787

AC:

AN:

1397276

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

689220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31444

American (AMR)

AF:

0.00

AC:

AN:

35648

Ashkenazi Jewish (ASJ)

AF:

0.0000398

AC:

AN:

25128

East Asian (EAS)

AF:

0.00

AC:

AN:

35670

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00000742

AC:

AN:

1078340

Other (OTH)

AF:

0.0000173

AC:

AN:

57932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

AF:

0.0000197

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67970

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurodevelopmental disorder

Pathogenic:1

Apr 06, 2020

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spinocerebellar ataxia type 21

Pathogenic:1

Oct 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Dec 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 171 of the TMEM240 protein (p.Arg171Trp). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 25070513). ClinVar contains an entry for this variant (Variation ID: 161196). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Benign

0.14

Eigen_PC

Benign

0.093

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.96

.;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.81

L;L

PhyloP100

1.6

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.28

Loss of solvent accessibility (P = 0.0036);Loss of solvent accessibility (P = 0.0036);

MVP

0.46

ClinPred

0.92

GERP RS

1.9

Varity_R

0.38

gMVP

0.53

Mutation Taster

=6/94

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over