1-1535427-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001114748.2(TMEM240):c.454G>A(p.Ala152Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,549,654 control chromosomes in the GnomAD database, including 1,069 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A152A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.026 (98 hom., cov: 32)
  • Exomes 𝑓: 0.034 (971 hom.)
• Consequence: TMEM240 NM_001114748.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.301

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001060605).
• BP6: Variant 1-1535427-C-T is Benign according to our data. Variant chr1-1535427-C-T is described in ClinVar as [Benign]. Clinvar id is 1235425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0258 (3925/152222) while in subpopulation NFE AF= 0.0325 (2212/67990). AF 95% confidence interval is 0.0314. There are 98 homozygotes in gnomad4. There are 2059 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3924 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM240	NM_001114748.2	c.454G>A	p.Ala152Thr	missense_variant	4/4	ENST00000378733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM240	ENST00000378733.9	c.454G>A	p.Ala152Thr	missense_variant	4/4	2	NM_001114748.2	P1

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3924 AN: 152112 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.00625

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0541

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0320 AC: 4734 AN: 147844 Hom.: 122 AF XY: 0.0329 AC XY: 2594 AN XY: 78960

Gnomad AFR exome AF: 0.00386

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.000185

Gnomad SAS exome AF: 0.0355

Gnomad FIN exome AF: 0.0753

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0345 AC: 48205 AN: 1397432 Hom.: 971 Cov.: 33 AF XY: 0.0345 AC XY: 23776 AN XY: 689266

Gnomad4 AFR exome AF: 0.00498

Gnomad4 AMR exome AF: 0.00905

Gnomad4 ASJ exome AF: 0.0531

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.0370

Gnomad4 FIN exome AF: 0.0701

Gnomad4 NFE exome AF: 0.0353

Gnomad4 OTH exome AF: 0.0318

GnomAD4 genome AF: 0.0258 AC: 3925 AN: 152222 Hom.: 98 Cov.: 32 AF XY: 0.0277 AC XY: 2059 AN XY: 74430

Gnomad4 AFR AF: 0.00623

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.0541

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0323

Gnomad4 FIN AF: 0.0774

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0308 Hom.: 59

Bravo AF: 0.0209

TwinsUK AF: 0.0334 AC: 124

ALSPAC AF: 0.0397 AC: 153

ExAC AF: 0.0333 AC: 832

Asia WGS AF: 0.0140 AC: 48 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	13
Dann	Benign	0.81
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.082	N
MetaRNN	Benign	0.0011	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.91	N;N
REVEL	Benign	0.040
Sift	Benign	0.62	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.014	B;B
Vest4		0.023
ClinPred		0.00096	T
GERP RS		-0.46
Varity_R		0.038
gMVP		0.27

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: rs146206869; hg19: chr1-1470807; COSMIC: COSV59236461; COSMIC: COSV59236461;