Genetic Variant NM_001114748.2:c.343G>C (chr1-1535619-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001114748.2(TMEM240):c.343G>C(p.Val115Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000716 in 1,397,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. V115M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

TMEM240
NM_001114748.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.75

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21752644).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM240	NM_001114748.2 link	c.343G>C	p.Val115Leu	missense_variant	Exon 3 of 4	ENST00000378733.9	NP_001108220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM240	ENST00000378733.9 link	c.343G>C	p.Val115Leu	missense_variant	Exon 3 of 4	2	NM_001114748.2	ENSP00000368007.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000656

AC:

AN:

152334

AF XY:

0.0000123

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:

0.0000175

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000716

AC:

AN:

1397412

Hom.:

Cov.:

AF XY:

0.00000870

AC XY:

AN XY:

689276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31570

American (AMR)

AF:

0.00

AC:

AN:

35680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25138

East Asian (EAS)

AF:

0.00

AC:

AN:

35706

South Asian (SAS)

AF:

0.00

AC:

AN:

79230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000927

AC:

AN:

1078494

Other (OTH)

AF:

0.00

AC:

AN:

57944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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.:

Alfa

AF:

0.0000565

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.066

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.83

.;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N

PhyloP100

2.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.26

Sift

Benign

0.20

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.57

P;P

Vest4

0.30

MutPred

0.20

Loss of catalytic residue at V115 (P = 0.0752);Loss of catalytic residue at V115 (P = 0.0752);

MVP

0.072

ClinPred

0.67

GERP RS

3.4

Varity_R

0.20

gMVP

0.70

Mutation Taster

=73/27

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over