16-75542641-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_001077418.3(TMEM231):c.625G>A(p.Asp209Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,613,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 3.81

Publications

7 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:

ENSG00000260092 (HGNC:):

ENSG00000260092 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-75542641-C-T is Pathogenic according to our data. Variant chr16-75542641-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39822.

BP4

Computational evidence support a benign effect (MetaRNN=0.34586817). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMEM231	NM_001077418.3 link	c.625G>A	p.Asp209Asn	missense_variant	Exon 5 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2 link	c.784G>A	p.Asp262Asn	missense_variant	Exon 4 of 6		NP_001070884.2
TMEM231	NR_074083.2 link	n.791G>A		non_coding_transcript_exon_variant	Exon 5 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TMEM231	ENST00000258173.11 link	c.625G>A	p.Asp209Asn	missense_variant	Exon 5 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5 link	c.712G>A	p.Asp238Asn	missense_variant	Exon 4 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5 link	c.481G>A	p.Asp161Asn	missense_variant	Exon 4 of 6	5		ENSP00000457254.1
ENSG00000260092	ENST00000460606.1 link	n.118G>A		non_coding_transcript_exon_variant	Exon 2 of 5	1		ENSP00000457544.1
TMEM231	ENST00000562410.5 link	n.*427G>A		non_coding_transcript_exon_variant	Exon 5 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5 link	n.*5G>A		non_coding_transcript_exon_variant	Exon 5 of 7	5		ENSP00000455520.1
TMEM231	ENST00000562410.5 link	n.*427G>A		3_prime_UTR_variant	Exon 5 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5 link	n.*5G>A		3_prime_UTR_variant	Exon 5 of 7	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000682

AC:

AN:

249258

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.0000431

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000540

AC:

AN:

1111838

Other (OTH)

AF:

0.0000331

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000474

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000827

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Pathogenic:2

Jun 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 262 of the TMEM231 protein (p.Asp262Asn). This variant is present in population databases (rs200799769, gnomAD 0.01%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 23012439, 27449316). 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 Asp209Asn. ClinVar contains an entry for this variant (Variation ID: 39822). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Feb 08, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23012439, 27449316, 26477546) -

Jul 20, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome and related disorders

Pathogenic:1

Feb 01, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TMEM231 c.784G>A (p.Asp262Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 249258 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TMEM231 causing Joubert Syndrome And Related Disorders (6.8e-05 vs 0.0004), allowing no conclusion about variant significance. c.784G>A has been reported in the literature in multiple individuals affected with Joubert Syndrome And Related Disorders (e.g., Srour_2012, Maglic_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -

TMEM231-related disorder

Pathogenic:1

Mar 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TMEM231 c.784G>A variant is predicted to result in the amino acid substitution p.Asp262Asn. This variant can also be referred to as (NM_001077418.1:c.625G>A (p.Asp209Asn). This variant, along with a protein truncating variant has been previously identified in three individuals with Joubert syndrome (JS) from two different families (Srour et al. 2012. PubMed ID: 23012439). Also, this variant along with an exonic deletion has been reported in three affected individuals with JS (Maglic et al. 2016. PubMed ID: 27449316). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Joubert syndrome 20

Pathogenic:1

Oct 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Uncertain:1

Jun 16, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.712G>A (p.D238N) alteration is located in exon 4 (coding exon 4) of the TMEM231 gene. This alteration results from a G to A substitution at nucleotide position 712, causing the aspartic acid (D) at amino acid position 238 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.13

T;.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.17

Sift

Benign

0.20

T;.;T

Sift4G

Uncertain

0.039

D;D;T

Polyphen

0.079

B;.;.

Vest4

0.34

MVP

0.28

MPC

0.012

ClinPred

0.32

GERP RS

2.3

Varity_R

0.056

gMVP

0.46

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over