1-1535618-A-G

Variant names:

• chr1-1535618-A-G
• rs948435492
• NM_001114748.2:c.344T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001114748.2(TMEM240):​c.344T>C​(p.Val115Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,397,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). 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: 7.2e-7 (0 hom.)
• Consequence: TMEM240 NM_001114748.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.56
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4070782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM240	NM_001114748.2	c.344T>C	p.Val115Ala	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	c.344T>C	p.Val115Ala	missense_variant	Exon 3 of 4	2	NM_001114748.2	ENSP00000368007.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397440 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689292

African (AFR) AF: 0.00 AC: 0 AN: 31570

American (AMR) AF: 0.00 AC: 0 AN: 35680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25138

East Asian (EAS) AF: 0.00 AC: 0 AN: 35706

South Asian (SAS) AF: 0.00 AC: 0 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078502

Other (OTH) AF: 0.0000173 AC: 1 AN: 57944

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Apr 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TMEM240 c.344T>C (p.Val115Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 152346 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.344T>C has been reported in the literature in at-least one heterozygous individual with cerebellar atrophy and progressive cerebellar ataxia in their forties whose variant was inherited from a parent who had not been clinically evaluated (example: Sun_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Spinocerebellar Ataxia Type 21. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29915382). ClinVar contains an entry for this variant (Variation ID: 437011). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Dec 17, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.65	.;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		5.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.0010	B;B
Vest4		0.73
MutPred		0.21		Loss of MoRF binding (P = 0.114);Loss of MoRF binding (P = 0.114);
MVP		0.061
ClinPred		0.83	D
GERP RS		2.2
Varity_R		0.26
gMVP		0.71
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs948435492; hg19: chr1-1470998;