rs606231455

Variant names:

• chr1-1535370-G-A
• rs606231455
• NM_001114748.2:c.511C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-1535370-G-A
• chr1-1535370-G-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP3_Moderate PP5 BS2

The NM_001114748.2(TMEM240):​c.511C>T​(p.Arg171Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000904 in 1,549,298 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: TMEM240 NM_001114748.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.59
• Publications: 3 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: Likely_benign. The variant received -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 1-1535370-G-A is Pathogenic according to our data. Variant chr1-1535370-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161196.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

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.511C>T	p.Arg171Trp	missense	Exon 4 of 4	NP_001108220.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM240	ENST00000378733.9	TSL:2 MANE Select	c.511C>T	p.Arg171Trp	missense	Exon 4 of 4	ENSP00000368007.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152022 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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000787 AC: 11 AN: 1397276 Hom.: 0 Cov.: 33 AF XY: 0.00000435 AC XY: 3 AN XY: 689220

African (AFR) AF: 0.00 AC: 0 AN: 31444

American (AMR) AF: 0.00 AC: 0 AN: 35648

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25128

East Asian (EAS) AF: 0.00 AC: 0 AN: 35670

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000742 AC: 8 AN: 1078340

Other (OTH) AF: 0.0000173 AC: 1 AN: 57932

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder (1)
-	1	-	not provided (1)
1	-	-	Spinocerebellar ataxia type 21 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.093
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.28		Loss of solvent accessibility (P = 0.0036)
MVP		0.46
ClinPred		0.92	D
GERP RS		1.9
Varity_R		0.38
gMVP		0.53
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs606231455; hg19: chr1-1470750; COSMIC: COSV59235425; COSMIC: COSV59235425;