dbSNP rs191125006: TMEM237:p.Ala116Ala (chr2-201633358-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

2 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: Ambry Genetics, G2P, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
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 -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 VariationId is 198116.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	NM_001044385.3	MANE Select	c.348G>A	p.Ala116Ala	synonymous	Exon 6 of 13	NP_001037850.1	Q96Q45-1
	TMEM237	NM_152388.4		c.324G>A	p.Ala108Ala	synonymous	Exon 6 of 13	NP_689601.2	Q96Q45-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM237	ENST00000409883.7	TSL:5 MANE Select	c.348G>A	p.Ala116Ala	synonymous	Exon 6 of 13	ENSP00000386264.2	Q96Q45-1
TMEM237	ENST00000621467.5	TSL:1	c.222G>A	p.Ala74Ala	synonymous	Exon 6 of 13	ENSP00000480508.2	A0A087WWU1
TMEM237	ENST00000466641.5	TSL:1	n.46G>A		non_coding_transcript_exon	Exon 1 of 6

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

GnomAD2 exomes

AF:

0.00164

AC:

363

AN:

222006

AF XY:

0.00152

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 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

African (AFR)

AF:

0.000333

AC:

AN:

33070

American (AMR)

AF:

0.00130

AC:

AN:

42356

Ashkenazi Jewish (ASJ)

AF:

0.000699

AC:

AN:

25736

East Asian (EAS)

AF:

0.000102

AC:

AN:

39164

South Asian (SAS)

AF:

0.000109

AC:

AN:

82640

European-Finnish (FIN)

AF:

0.000172

AC:

AN:

52292

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00380

AC:

4194

AN:

1102532

Other (OTH)

AF:

0.00249

AC:

149

AN:

59720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

209

418

626

835

1044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<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:

0.00160

AC:

243

AN:

152164

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.000939

AC:

AN:

41514

American (AMR)

AF:

0.000915

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00269

AC:

183

AN:

67992

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00246

Hom.:

Bravo

AF:

0.00173

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Joubert syndrome 14 (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over