chr16-75555872-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001077418.3(TMEM231):c.241C>T(p.Leu81Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000672 in 1,591,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 4.04

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-75555872-G-A is Pathogenic according to our data. Variant chr16-75555872-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445818.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.241C>T	p.Leu81Phe	missense_variant	Exon 2 of 7	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.400C>T	p.Leu134Phe	missense_variant	Exon 1 of 6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.284C>T		non_coding_transcript_exon_variant	Exon 2 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM231	ENST00000258173.11 link	c.241C>T	p.Leu81Phe	missense_variant	Exon 2 of 7	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5 link	c.328C>T	p.Leu110Phe	missense_variant	Exon 1 of 6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5 link	c.241C>T	p.Leu81Phe	missense_variant	Exon 2 of 6	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 link	n.241C>T		non_coding_transcript_exon_variant	Exon 2 of 7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.241C>T		non_coding_transcript_exon_variant	Exon 2 of 7	5		ENSP00000455520.1	H3BPY4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000188

AC:

AN:

212802

Hom.:

AF XY:

0.00000862

AC XY:

AN XY:

116002

show subpopulations

Gnomad AFR exome

AF:

0.0000838

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000317

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000716

AC:

103

AN:

1438970

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

713190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000258

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000917

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Pathogenic:1

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 134 of the TMEM231 protein (p.Leu134Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 25869670). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.241C>T (p.Leu81Phe). ClinVar contains an entry for this variant (Variation ID: 445818). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects TMEM231 function (PMID: 25869670). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Ciliopathy

Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Joubert syndrome 20

Pathogenic:1

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Homozygote Missense variant c.400C>T in Exon 1 of the TMEM231 gene that results in the amino acid substitution p.Leu134Phe was identified. The observed variant has a minor allele frequency of 0.00002 in gnomAD exomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as LikelyPathogenic (Variant ID: 445818). This missense variant has been observed in individual(s) with clinical features of Joubert syndrome. Experimental studies have shown that this missense change affects TMEM231 gene function (Roberson EC et al., 2015). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

not provided

Uncertain:1

May 08, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TMEM231-related disorder

Uncertain:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TMEM231 c.400C>T variant is predicted to result in the amino acid substitution p.Leu134Phe. This variant was reported as c.241C>T in two related individuals with orofacial dysmorphism alongside another variant reported as c.373C>G (Braun et al. 2015. PubMed ID: 26489029; Roberson et al. 2015. PubMed ID: 25869670) and in one individual with a retinal disease (Sharon et al. 2019. PubMed ID: 31456290). This variant is reported in 0.0084% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may well be pathogenic, it is interpreted as uncertain at this time due to lack of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;.;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.85

T;T;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

-0.081

MutationAssessor

Uncertain

2.3

M;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;.;N

REVEL

Uncertain

0.53

Sift

Uncertain

0.0060

D;.;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.99

D;.;.

Vest4

0.66

MVP

0.53

MPC

1.9

ClinPred

0.85

GERP RS

5.9

Varity_R

0.41

gMVP

0.42

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