rs73989521

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001044385.3(TMEM237):c.1096G>T(p.Ala366Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,608,098 control chromosomes in the GnomAD database, including 2,715 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.075 ( 649 hom., cov: 31)

Exomes 𝑓: 0.049 ( 2066 hom. )

Consequence

TMEM237
NM_001044385.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.766

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018060207).

BP6

Variant 2-201626089-C-A is Benign according to our data. Variant chr2-201626089-C-A is described in ClinVar as [Benign]. Clinvar id is 130592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201626089-C-A is described in Lovd as [Benign]. Variant chr2-201626089-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM237	NM_001044385.3 linkuse as main transcript	c.1096G>T	p.Ala366Ser	missense_variant	12/13	ENST00000409883.7	NP_001037850.1
TMEM237	NM_152388.4 linkuse as main transcript	c.1072G>T	p.Ala358Ser	missense_variant	12/13		NP_689601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM237	ENST00000409883.7 linkuse as main transcript	c.1096G>T	p.Ala366Ser	missense_variant	12/13	5	NM_001044385.3	ENSP00000386264	P4	Q96Q45-1

Frequencies

GnomAD3 genomes

AF:

0.0754

AC:

11444

AN:

151746

Hom.:

649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.153

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0555

Gnomad ASJ

AF:

0.0496

Gnomad EAS

AF:

0.000967

Gnomad SAS

AF:

0.0163

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0546

Gnomad OTH

AF:

0.0689

GnomAD3 exomes

AF:

0.0444

AC:

10726

AN:

241314

Hom.:

370

AF XY:

0.0434

AC XY:

5664

AN XY:

130574

show subpopulations

Gnomad AFR exome

AF:

0.155

Gnomad AMR exome

AF:

0.0319

Gnomad ASJ exome

AF:

0.0501

Gnomad EAS exome

AF:

0.000228

Gnomad SAS exome

AF:

0.0159

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.0530

Gnomad OTH exome

AF:

0.0430

GnomAD4 exome

AF:

0.0493

AC:

71782

AN:

1456234

Hom.:

2066

Cov.:

AF XY:

0.0482

AC XY:

34901

AN XY:

723718

show subpopulations

Gnomad4 AFR exome

AF:

0.155

Gnomad4 AMR exome

AF:

0.0344

Gnomad4 ASJ exome

AF:

0.0495

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0173

Gnomad4 FIN exome

AF:

0.0173

Gnomad4 NFE exome

AF:

0.0524

Gnomad4 OTH exome

AF:

0.0497

GnomAD4 genome

AF:

0.0754

AC:

11450

AN:

151864

Hom.:

649

Cov.:

AF XY:

0.0721

AC XY:

5349

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.152

Gnomad4 AMR

AF:

0.0554

Gnomad4 ASJ

AF:

0.0496

Gnomad4 EAS

AF:

0.000969

Gnomad4 SAS

AF:

0.0163

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.0546

Gnomad4 OTH

AF:

0.0682

Alfa

AF:

0.0594

Hom.:

376

Bravo

AF:

0.0821

TwinsUK

AF:

0.0496

AC:

184

ALSPAC

AF:

0.0579

AC:

223

ESP6500AA

AF:

0.149

AC:

546

ESP6500EA

AF:

0.0537

AC:

439

ExAC

AF:

0.0461

AC:

5570

Asia WGS

AF:

0.0200

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joubert syndrome 14

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.011

.;T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;L;.

MutationTaster

Benign

0.0018

P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.032

Sift

Benign

0.22

T;T;.

Sift4G

Benign

0.24

T;T;T

Vest4

0.084

MPC

0.050

ClinPred

0.0047

GERP RS

2.0

Varity_R

0.040

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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