1-1535423-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001114748.2(TMEM240):c.458G>C(p.Gly153Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G153R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMEM240 NM_001114748.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM240	NM_001114748.2	c.458G>C	p.Gly153Ala	missense_variant	4/4	ENST00000378733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM240	ENST00000378733.9	c.458G>C	p.Gly153Ala	missense_variant	4/4	2	NM_001114748.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 13, 2022

This missense change has been observed in at least one individual who was not affected with TMEM240-related conditions (Invitae). This variant has not been reported in the literature in individuals affected with TMEM240-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 153 of the TMEM240 protein (p.Gly153Ala). 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. 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"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		0.99	D;D
Vest4		0.31
MutPred		0.41		Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);
MVP		0.067
ClinPred		0.88	D
GERP RS		2.9
Varity_R		0.31
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs1642198218; hg19: chr1-1470803;