1-1535449-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001114748.2(TMEM240):c.432G>A(p.Pro144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,549,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: TMEM240 NM_001114748.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-1535449-C-T is Benign according to our data. Variant chr1-1535449-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 717536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1535449-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BS2: High AC in GnomAd at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM240	NM_001114748.2	c.432G>A	p.Pro144=	synonymous_variant	4/4	ENST00000378733.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM240	ENST00000378733.9	c.432G>A	p.Pro144=	synonymous_variant	4/4	2	NM_001114748.2	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000171 AC: 25 AN: 146062 Hom.: 0 AF XY: 0.000115 AC XY: 9 AN XY: 78226

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000242 AC: 338 AN: 1396888 Hom.: 0 Cov.: 33 AF XY: 0.000254 AC XY: 175 AN XY: 689002

Gnomad4 AFR exome AF: 0.0000951

Gnomad4 AMR exome AF: 0.000196

Gnomad4 ASJ exome AF: 0.0000398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.000173

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74382

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000427

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000189

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	TMEM240: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	5.1
Dann	Benign	0.70

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: rs566100696; hg19: chr1-1470829; COSMIC: COSV59232093; COSMIC: COSV59232093;