chr2-201626089-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/20 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

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

Joubert syndrome 14
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with renal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMEM237 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 130592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001044385.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	NM_001044385.3	MANE Select	c.1096G>T	p.Ala366Ser	missense	Exon 12 of 13	NP_001037850.1
	TMEM237	NM_152388.4		c.1072G>T	p.Ala358Ser	missense	Exon 12 of 13	NP_689601.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM237	ENST00000409883.7	TSL:5 MANE Select	c.1096G>T	p.Ala366Ser	missense	Exon 12 of 13	ENSP00000386264.2
TMEM237	ENST00000621467.5	TSL:1	c.970G>T	p.Ala324Ser	missense	Exon 12 of 13	ENSP00000480508.2
TMEM237	ENST00000409444.6	TSL:5	c.1072G>T	p.Ala358Ser	missense	Exon 12 of 13	ENSP00000387203.2

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

GnomAD2 exomes

AF:

0.0444

AC:

10726

AN:

241314

AF XY:

0.0434

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 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

African (AFR)

AF:

0.155

AC:

5160

AN:

33358

American (AMR)

AF:

0.0344

AC:

1521

AN:

44154

Ashkenazi Jewish (ASJ)

AF:

0.0495

AC:

1287

AN:

26006

East Asian (EAS)

AF:

0.000101

AC:

AN:

39618

South Asian (SAS)

AF:

0.0173

AC:

1467

AN:

84928

European-Finnish (FIN)

AF:

0.0173

AC:

919

AN:

53208

Middle Eastern (MID)

AF:

0.0477

AC:

275

AN:

5760

European-Non Finnish (NFE)

AF:

0.0524

AC:

58160

AN:

1109006

Other (OTH)

AF:

0.0497

AC:

2989

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3122

6245

9367

12490

15612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2140

4280

6420

8560

10700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0754

AC:

11450

AN:

151864

Hom.:

649

Cov.:

AF XY:

0.0721

AC XY:

5349

AN XY:

74216

show subpopulations

African (AFR)

AF:

0.152

AC:

6305

AN:

41354

American (AMR)

AF:

0.0554

AC:

845

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.0496

AC:

172

AN:

3470

East Asian (EAS)

AF:

0.000969

AC:

AN:

5160

South Asian (SAS)

AF:

0.0163

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.0140

AC:

148

AN:

10552

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0546

AC:

3712

AN:

67964

Other (OTH)

AF:

0.0682

AC:

144

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

498

997

1495

1994

2492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0607

Hom.:

967

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Joubert syndrome 14 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.011

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

0.77

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

REVEL

Benign

0.032

Sift

Benign

0.22

Sift4G

Benign

0.24

Vest4

0.084

MPC

0.050

ClinPred

0.0047

GERP RS

2.0

Varity_R

0.040

gMVP

0.33

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over