rs377440297

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000568377.5(TMEM231):c.119C>T(p.Ser40Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,568,414 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict 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. S40S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 2 hom. )

Consequence

TMEM231
ENST00000568377.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.61

Publications

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

BP4

Computational evidence support a benign effect (MetaRNN=0.011699468).

BP6

Variant 16-75556081-G-A is Benign according to our data. Variant chr16-75556081-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287699.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.129C>T	p.Phe43Phe	synonymous_variant	Exon 1 of 7	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.191C>T	p.Ser64Phe	missense_variant	Exon 1 of 6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.172C>T		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM231	ENST00000568377.5 link	c.119C>T	p.Ser40Phe	missense_variant	Exon 1 of 6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000258173.11 link	c.129C>T	p.Phe43Phe	synonymous_variant	Exon 1 of 7	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000565067.5 link	c.129C>T	p.Phe43Phe	synonymous_variant	Exon 1 of 6	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 link	n.129C>T		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.129C>T		non_coding_transcript_exon_variant	Exon 1 of 7	5		ENSP00000455520.1	H3BPY4

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000497

AC:

AN:

169150

AF XY:

0.000529

show subpopulations

Gnomad AFR exome

AF:

0.000119

Gnomad AMR exome

AF:

0.000266

Gnomad ASJ exome

AF:

0.00260

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000676

Gnomad OTH exome

AF:

0.00152

GnomAD4 exome

AF:

0.000757

AC:

1072

AN:

1416054

Hom.:

Cov.:

AF XY:

0.000721

AC XY:

505

AN XY:

700348

show subpopulations

African (AFR)

AF:

0.0000931

AC:

AN:

32210

American (AMR)

AF:

0.000239

AC:

AN:

37702

Ashkenazi Jewish (ASJ)

AF:

0.00323

AC:

AN:

25354

East Asian (EAS)

AF:

0.00

AC:

AN:

36754

South Asian (SAS)

AF:

0.0000246

AC:

AN:

81146

European-Finnish (FIN)

AF:

0.0000410

AC:

AN:

48820

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.000844

AC:

920

AN:

1089686

Other (OTH)

AF:

0.000903

AC:

AN:

58708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

143

215

286

358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.000564

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000429

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

41598

American (AMR)

AF:

0.000327

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000794

AC:

AN:

68026

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000823

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000245

AC:

ExAC

AF:

0.000358

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Sep 19, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge -

Jun 09, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 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

- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TMEM231-related disorder

Benign:1

Feb 02, 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

Benign

0.20

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.95

Eigen

Benign

-0.15

Eigen_PC

Benign

0.014

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.42

M_CAP

Benign

0.055

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.87

PhyloP100

1.6

PrimateAI

Uncertain

0.74

Sift4G

Pathogenic

0.0

Vest4

0.21

MVP

0.14

MPC

1.8

ClinPred

0.094

GERP RS

4.5

PromoterAI

-0.20

Neutral

(source)

Mutation Taster

=88/12

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over