rs606231451

Positions:

• chr1-1535372-G-A
• chr1-1535372-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001114748.2(TMEM240):​c.509C>T​(p.Pro170Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,397,430 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P170S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TMEM240 NM_001114748.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.00

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746
• PP5: Variant 1-1535372-G-A is Pathogenic according to our data. Variant chr1-1535372-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1535372-G-A is described in Lovd as [Pathogenic]. Variant chr1-1535372-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM240	NM_001114748.2	c.509C>T	p.Pro170Leu	missense_variant	4/4	ENST00000378733.9	NP_001108220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM240	ENST00000378733.9	c.509C>T	p.Pro170Leu	missense_variant	4/4	2	NM_001114748.2	ENSP00000368007.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397430 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 689284

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia type 21 Pathogenic:8

Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -
Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 05, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: Variant is predicted to result in a missense amino acid change from proline to leucine. The mechanism of disease for this gene is not clearly established. However, gain of function is likely (PMID: 25070513). This gene is associated with autosomal dominant disease. Variant is absent from gnomAD (both v2 and v3). (SP) An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). Missense variant with conflicting in silico predictions and high conservation. This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as a recurrent variant in multiple unrelated individuals with spinocerebellar ataxia (PMIDs: 25070513, 33851480). It has also been reported as likely pathogenic/pathogenic in ClinVar. (SP) This variant has strong evidence for segregation with disease. It has been reported to segregate with disease in many affected individuals across three generations in two unrelated families (PMID: 25070513). (SP) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 12, 2024	PS2_VS, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	May 31, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, gain of function is likely (PMID: 25070513). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as a recurrent variant in multiple unrelated individuals with spinocerebellar ataxia (PMIDs: 25070513, 33851480). It has also been reported as likely pathogenic/pathogenic in ClinVar. (SP) 0901 - This variant has strong evidence for segregation with disease. It has been reported to segregate with disease in many affected individuals across three generations in two unrelated families (PMID: 25070513). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2023	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30522958, 30184469, 32816195, 25070513, 29687291, 26813285, 29915382, 31692161, 33669240, 33726816, 35872528, 34445196) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TMEM240: PS2:Very Strong, PM2 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Mar 28, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.078	B;B
Vest4		0.88
MutPred		0.17		Gain of MoRF binding (P = 0.014);Gain of MoRF binding (P = 0.014);
MVP		0.37
ClinPred		0.96	D
GERP RS		2.9
Varity_R		0.50
gMVP		0.52

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: rs606231451; hg19: chr1-1470752;