rs199813223

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001077418.3(TMEM231):c.710G>C(p.Arg237Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00147 in 1,612,202 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R237R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 4.62

Publications

3 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: Benign. The variant received -9 ACMG points.

BP6

Variant 16-75541410-C-G is Benign according to our data. Variant chr16-75541410-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 570416.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00132 (201/152194) while in subpopulation AMR AF = 0.00295 (45/15276). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.710G>C	p.Arg237Thr	missense_variant	Exon 6 of 7	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.869G>C	p.Arg290Thr	missense_variant	Exon 5 of 6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.876G>C		non_coding_transcript_exon_variant	Exon 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM231	ENST00000258173.11 link	c.710G>C	p.Arg237Thr	missense_variant	Exon 6 of 7	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5 link	c.797G>C	p.Arg266Thr	missense_variant	Exon 5 of 6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5 link	c.566G>C	p.Arg189Thr	missense_variant	Exon 5 of 6	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 link	n.*512G>C		non_coding_transcript_exon_variant	Exon 6 of 7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.*90G>C		non_coding_transcript_exon_variant	Exon 6 of 7	5		ENSP00000455520.1	H3BPY4
TMEM231	ENST00000562410.5 link	n.*512G>C		3_prime_UTR_variant	Exon 6 of 7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.*90G>C		3_prime_UTR_variant	Exon 6 of 7	5		ENSP00000455520.1	H3BPY4
ENSG00000260092	ENST00000460606.1 link	n.157+1192G>C		intron_variant	Intron 2 of 4	1		ENSP00000457544.1	H3BUA1

Frequencies

GnomAD3 genomes

AF:

0.00132

AC:

201

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00201

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00107

AC:

265

AN:

247738

AF XY:

0.000989

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000797

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.00149

AC:

2175

AN:

1460008

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

1024

AN XY:

726218

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33396

American (AMR)

AF:

0.00108

AC:

AN:

44526

Ashkenazi Jewish (ASJ)

AF:

0.000345

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.000116

AC:

AN:

86008

European-Finnish (FIN)

AF:

0.000506

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00180

AC:

2003

AN:

1110940

Other (OTH)

AF:

0.00108

AC:

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

103

205

308

410

513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00132

AC:

201

AN:

152194

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000362

AC:

AN:

41450

American (AMR)

AF:

0.00295

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00201

AC:

137

AN:

68030

Other (OTH)

AF:

0.000956

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00185

Hom.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00168

AC:

ExAC

AF:

0.00107

AC:

129

EpiCase

AF:

0.00120

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMEM231: BP4 -

Dec 13, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Uncertain:1Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TMEM231-related disorder

Benign:1

Aug 09, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.061

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

4.6

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.7

D;.;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.010

D;.;T

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.82

P;.;.

Vest4

0.76

MVP

0.50

MPC

0.043

ClinPred

0.11

GERP RS

4.4

Varity_R

0.24

gMVP

0.74

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: 45

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