1-1535424-C-T

Variant names:

• chr1-1535424-C-T
• rs1353028252
• NM_001114748.2:c.457G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001114748.2(TMEM240):​c.457G>A​(p.Gly153Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,549,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G153A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TMEM240 NM_001114748.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.28

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM240	NM_001114748.2	c.457G>A	p.Gly153Arg	missense_variant	Exon 4 of 4	ENST00000378733.9	NP_001108220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM240	ENST00000378733.9	c.457G>A	p.Gly153Arg	missense_variant	Exon 4 of 4	2	NM_001114748.2	ENSP00000368007.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 31

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000135 AC: 2 AN: 148048 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 79038

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000442

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1397506 Hom.: 0 Cov.: 33 AF XY: 0.0000145 AC XY: 10 AN XY: 689312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0000631

Gnomad4 FIN exome AF: 0.0000208

Gnomad4 NFE exome AF: 0.00000742

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74280

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jan 02, 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.457G>A (p.Gly153Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 148048 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.457G>A has been reported in the literature in at-least one individual affected with Ataxia (example: ElNaofal_2023) . 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 has been ascertained in the context of this evaluation (PMID: 36703223). ClinVar contains an entry for this variant (Variation ID: 1809675). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Dec 17, 2022

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		1.0	D;D
Vest4		0.37
MutPred		0.39		Gain of MoRF binding (P = 0.004);Gain of MoRF binding (P = 0.004);
MVP		0.36
ClinPred		0.79	D
GERP RS		2.9
Varity_R		0.48
gMVP		0.58

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: rs1353028252; hg19: chr1-1470804; COSMIC: COSV59232262; COSMIC: COSV59232262;