16-75556024-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001077416.2(TMEM231):c.248C>A(p.Ser83*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,569,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S83S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

TMEM231
NM_001077416.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.0230

Publications

1 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 16-75556024-G-T is Pathogenic according to our data. Variant chr16-75556024-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 565503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077416.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM231	NM_001077418.3	MANE Select	c.139+47C>A		intron	N/A	NP_001070886.1
TMEM231	NM_001077416.2		c.248C>A	p.Ser83*	stop_gained	Exon 1 of 6	NP_001070884.2
TMEM231	NR_074083.2		n.182+47C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM231	ENST00000568377.5	TSL:1	c.176C>A	p.Ser59*	stop_gained	Exon 1 of 6	ENSP00000476267.1
TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.139+47C>A		intron	N/A	ENSP00000258173.5
TMEM231	ENST00000565067.5	TSL:5	c.139+47C>A		intron	N/A	ENSP00000457254.1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000225

AC:

AN:

177604

AF XY:

0.000268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000227

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000575

Gnomad NFE exome

AF:

0.000420

Gnomad OTH exome

AF:

0.000424

GnomAD4 exome

AF:

0.000287

AC:

407

AN:

1417486

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

186

AN XY:

700782

show subpopulations

African (AFR)

AF:

0.0000930

AC:

AN:

32248

American (AMR)

AF:

0.000157

AC:

AN:

38226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25238

East Asian (EAS)

AF:

0.00

AC:

AN:

37162

South Asian (SAS)

AF:

0.00

AC:

AN:

81240

European-Finnish (FIN)

AF:

0.0000606

AC:

AN:

49494

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.000342

AC:

373

AN:

1089616

Other (OTH)

AF:

0.000376

AC:

AN:

58576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000276

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41406

American (AMR)

AF:

0.000851

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000468

Hom.:

Bravo

AF:

0.000295

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000493

AC:

ExAC

AF:

0.000118

AC:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 (2)

Inborn genetic diseases (1)

Joubert syndrome and related disorders (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

0.12

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.045

PhyloP100

-0.023

Vest4

0.056

GERP RS

0.17

PromoterAI

0.17

Neutral

(source)

Mutation Taster

=25/175

disease causing (ClinVar)

(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