rs200063331

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_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 (★★). 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:4

Conservation

PhyloP100: -0.0230

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 links:

ENSG00000259992 (HGNC:):

ENSG00000259992 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.139+47C>A		intron_variant	Intron 1 of 6	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.248C>A	p.Ser83*	stop_gained	Exon 1 of 6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.182+47C>A		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM231	ENST00000568377.5 link	c.176C>A	p.Ser59*	stop_gained	Exon 1 of 6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000258173.11 link	c.139+47C>A		intron_variant	Intron 1 of 6	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000565067.5 link	c.139+47C>A		intron_variant	Intron 1 of 5	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 link	n.139+47C>A		intron_variant	Intron 1 of 6	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.139+47C>A		intron_variant	Intron 1 of 6	5		ENSP00000455520.1	H3BPY4

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

GnomAD3 exomes

AF:

0.000225

AC:

AN:

177604

Hom.:

AF XY:

0.000268

AC XY:

AN XY:

97102

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000930

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000606

Gnomad4 NFE exome

AF:

0.000342

Gnomad4 OTH exome

AF:

0.000376

GnomAD4 genome

AF:

0.000276

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.000295

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000493

AC:

ExAC

AF:

0.000118

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2025	This sequence change creates a premature translational stop signal (p.Ser83*) in the TMEM231 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM231 are known to be pathogenic (PMID: 23012439, 23349226). This variant is present in population databases (rs200063331, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TMEM231-related conditions. ClinVar contains an entry for this variant (Variation ID: 565503). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2022

The c.176C>A (p.S59*) alteration, located in exon 1 (coding exon 1) of the TMEM231 gene, consists of a C to A substitution at nucleotide position 176. This changes the amino acid from a serine (S) to a stop codon at amino acid position 59. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as likely pathogenic. -

Joubert syndrome and related disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 22, 2024

Variant summary: TMEM231 c.248C>A (p.Ser83X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00023 in 177604 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TMEM231 causing Joubert Syndrome And Related Disorders (0.00023 vs 0.0004), allowing no conclusion about variant significance. To the best of our knowledge, c.248C>A has been not reported in the literature in individuals affected with Joubert Syndrome And Related Disorders, but in an individual with Congenital Stationary Night Blindness, this variant was reported as an additional finding, together with a pathogenic NYX variant that may fully explain the eye phenotype (Zhu_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35456422). ClinVar contains an entry for this variant (Variation ID: 565503). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

0.12

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.045

Vest4

0.056

GERP RS

0.17

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

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