16-75556194-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001077418.3(TMEM231):c.16C>G(p.Leu6Val) variant causes a missense change. The variant allele was found at a frequency of 0.0938 in 1,485,022 control chromosomes in the GnomAD database, including 19,435 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L6I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 2663 hom., cov: 33)

Exomes 𝑓: 0.091 ( 16772 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.96

Publications

23 publications found

Variant links:

Genes affected

TMEM231 (HGNC:37234): (transmembrane protein 231) This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

TMEM231 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Joubert syndrome 20
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
orofaciodigital syndrome III
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMEM231 links:

ENSG00000259992 (HGNC:):

ENSG00000259992 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=1.8012524E-5).

BP6

Variant 16-75556194-G-C is Benign according to our data. Variant chr16-75556194-G-C is described in ClinVar as Benign. ClinVar VariationId is 130587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077418.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM231	NM_001077418.3	MANE Select	c.16C>G	p.Leu6Val	missense	Exon 1 of 7	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2		c.78C>G	p.Ser26Arg	missense	Exon 1 of 6	NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2		n.59C>G		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.16C>G	p.Leu6Val	missense	Exon 1 of 7	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5	TSL:1	c.6C>G	p.Ser2Arg	missense	Exon 1 of 6	ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5	TSL:5	c.16C>G	p.Leu6Val	missense	Exon 1 of 6	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18175

AN:

152146

Hom.:

2652

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0929

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.709

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.0581

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0477

Gnomad OTH

AF:

0.126

GnomAD2 exomes

AF:

0.210

AC:

24008

AN:

114184

AF XY:

0.196

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.438

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.751

Gnomad FIN exome

AF:

0.0584

Gnomad NFE exome

AF:

0.0520

Gnomad OTH exome

AF:

0.158

GnomAD4 exome

AF:

0.0908

AC:

121014

AN:

1332758

Hom.:

16772

Cov.:

AF XY:

0.0945

AC XY:

61597

AN XY:

651754

show subpopulations

African (AFR)

AF:

0.0918

AC:

2616

AN:

28502

American (AMR)

AF:

0.399

AC:

11201

AN:

28060

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

2394

AN:

20028

East Asian (EAS)

AF:

0.719

AC:

25324

AN:

35242

South Asian (SAS)

AF:

0.274

AC:

18876

AN:

68902

European-Finnish (FIN)

AF:

0.0551

AC:

2035

AN:

36938

Middle Eastern (MID)

AF:

0.0931

AC:

494

AN:

5304

European-Non Finnish (NFE)

AF:

0.0486

AC:

51267

AN:

1054540

Other (OTH)

AF:

0.123

AC:

6807

AN:

55242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

5116

10232

15348

20464

25580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2500

5000

7500

10000

12500

<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:

0.120

AC:

18216

AN:

152264

Hom.:

2663

Cov.:

AF XY:

0.132

AC XY:

9802

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0934

AC:

3879

AN:

41544

American (AMR)

AF:

0.293

AC:

4482

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

474

AN:

3472

East Asian (EAS)

AF:

0.710

AC:

3671

AN:

5172

South Asian (SAS)

AF:

0.304

AC:

1465

AN:

4822

European-Finnish (FIN)

AF:

0.0581

AC:

617

AN:

10620

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0477

AC:

3244

AN:

68030

Other (OTH)

AF:

0.127

AC:

268

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

665

1331

1996

2662

3327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<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:

0.0786

Hom.:

1200

Bravo

AF:

0.140

TwinsUK

AF:

0.0464

AC:

172

ALSPAC

AF:

0.0467

AC:

180

ESP6500AA

AF:

0.0835

AC:

301

ESP6500EA

AF:

0.0463

AC:

361

ExAC

AF:

0.156

AC:

17902

Asia WGS

AF:

0.449

AC:

1557

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 20 (1)

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.060

Eigen

Benign

-0.038

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.83

MetaRNN

Benign

0.000018

MetaSVM

Benign

-0.92

PhyloP100

4.0

PROVEAN

Benign

0.86

REVEL

Benign

0.099

Sift

Benign

1.0

Sift4G

Benign

0.78

Polyphen

0.021

Vest4

0.045

ClinPred

0.075

GERP RS

4.6

PromoterAI

0.043

Neutral

(source)

Varity_R

0.11

gMVP

0.46

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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