1-1535428-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001114748.2(TMEM240):c.453C>T(p.Ala151=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,549,496 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (45 hom.)
• Consequence: TMEM240 NM_001114748.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.293

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-1535428-G-A is Benign according to our data. Variant chr1-1535428-G-A is described in ClinVar as [Benign]. Clinvar id is 593226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1535428-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.293 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00704 (1070/152076) while in subpopulation AFR AF= 0.00892 (370/41476). AF 95% confidence interval is 0.00817. There are 2 homozygotes in gnomad4. There are 507 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1070 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM240	NM_001114748.2	c.453C>T	p.Ala151=	synonymous_variant	4/4	ENST00000378733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM240	ENST00000378733.9	c.453C>T	p.Ala151=	synonymous_variant	4/4	2	NM_001114748.2	P1

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1070 AN: 151968 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00839

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00416 AC: 615 AN: 147878 Hom.: 2 AF XY: 0.00423 AC XY: 334 AN XY: 78988

Gnomad AFR exome AF: 0.00799

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00146

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.00694

Gnomad OTH exome AF: 0.00498

GnomAD4 exome AF: 0.00583 AC: 8141 AN: 1397420 Hom.: 45 Cov.: 33 AF XY: 0.00572 AC XY: 3944 AN XY: 689260

Gnomad4 AFR exome AF: 0.00894

Gnomad4 AMR exome AF: 0.00311

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00481

Gnomad4 NFE exome AF: 0.00655

Gnomad4 OTH exome AF: 0.00499

GnomAD4 genome AF: 0.00704 AC: 1070 AN: 152076 Hom.: 2 Cov.: 32 AF XY: 0.00682 AC XY: 507 AN XY: 74342

Gnomad4 AFR AF: 0.00892

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00837

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00710 Hom.: 4

Bravo AF: 0.00713

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TMEM240: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	4.1
Dann	Benign	0.66

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: rs199556012; hg19: chr1-1470808;