2-201633358-C-T

Position:

chr2-201633358-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001044385.3(TMEM237):c.348G>A(p.Ala116Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,595,414 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 13 hom. )

Consequence

TMEM237
NM_001044385.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 0.365

Variant links:

Genes affected

TMEM237 (HGNC:14432): (transmembrane protein 237) The protein encoded by this gene is a tetraspanin protein that is thought to be involved in WNT signaling. Defects in this gene are a cause of Joubert syndrome-14. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

TMEM237 links:

TMEM237 (HGNC:):

TMEM237 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 2-201633358-C-T is Benign according to our data. Variant chr2-201633358-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198116.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}. Variant chr2-201633358-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.365 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0016 (243/152164) while in subpopulation NFE AF= 0.00269 (183/67992). AF 95% confidence interval is 0.00237. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM237	NM_001044385.3 linkuse as main transcript	c.348G>A	p.Ala116Ala	synonymous_variant	6/13	ENST00000409883.7	NP_001037850.1	Q96Q45-1
TMEM237	NM_152388.4 linkuse as main transcript	c.324G>A	p.Ala108Ala	synonymous_variant	6/13		NP_689601.2	Q96Q45-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM237	ENST00000409883.7 linkuse as main transcript	c.348G>A	p.Ala116Ala	synonymous_variant	6/13	5	NM_001044385.3	ENSP00000386264.2		Q96Q45-1

Frequencies

GnomAD3 genomes

AF:

0.00160

AC:

243

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00269

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00164

AC:

363

AN:

222006

Hom.:

AF XY:

0.00152

AC XY:

181

AN XY:

119226

show subpopulations

Gnomad AFR exome

AF:

0.000444

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.000738

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.0000985

Gnomad NFE exome

AF:

0.00290

Gnomad OTH exome

AF:

0.00235

GnomAD4 exome

AF:

0.00308

AC:

4451

AN:

1443250

Hom.:

Cov.:

AF XY:

0.00301

AC XY:

2155

AN XY:

716046

show subpopulations

Gnomad4 AFR exome

AF:

0.000333

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.000699

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.000109

Gnomad4 FIN exome

AF:

0.000172

Gnomad4 NFE exome

AF:

0.00380

Gnomad4 OTH exome

AF:

0.00249

GnomAD4 genome

AF:

0.00160

AC:

243

AN:

152164

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.000939

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00269

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00246

Hom.:

Bravo

AF:

0.00173

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	TMEM237: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Joubert syndrome 14

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over