1-1535723-G-T

Variant names:

• chr1-1535723-G-T
• rs606231454
• NM_001114748.2:c.239C>A
• TMEM240 p.Thr80Lys

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001114748.2(TMEM240):​c.239C>A​(p.Thr80Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000129 in 1,550,376 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T80M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TMEM240 NM_001114748.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.62
• Publications: 7 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-1535723-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161195.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114748.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM240	NM_001114748.2	MANE Select	c.239C>A	p.Thr80Lys	missense	Exon 3 of 4	NP_001108220.1	Q5SV17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM240	ENST00000378733.9	TSL:2 MANE Select	c.239C>A	p.Thr80Lys	missense	Exon 3 of 4	ENSP00000368007.4	Q5SV17

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398198 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 689652

African (AFR) AF: 0.00 AC: 0 AN: 31582

American (AMR) AF: 0.00 AC: 0 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48414

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078728

Other (OTH) AF: 0.00 AC: 0 AN: 57966

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	28
DANN	Benign	0.90
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.43
Sift	Benign	0.064	T
Sift4G	Benign	0.12	T
Varity_R		0.27
gMVP		0.81
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs606231454;

hg19: chr1-1471103;