16-75555872-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_001077418.3(TMEM231):c.241C>G(p.Leu81Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,438,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L81F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.04

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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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 submission is: [Conflicting_classifications_of_pathogenicity].

BP4

Computational evidence support a benign effect (MetaRNN=0.28885084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.241C>G	p.Leu81Val	missense_variant	Exon 2 of 7	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.400C>G	p.Leu134Val	missense_variant	Exon 1 of 6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.284C>G		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>G	p.Leu81Val	missense_variant	Exon 2 of 7	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5 link	c.328C>G	p.Leu110Val	missense_variant	Exon 1 of 6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5 link	c.241C>G	p.Leu81Val	missense_variant	Exon 2 of 6	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 link	n.241C>G		non_coding_transcript_exon_variant	Exon 2 of 7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.241C>G		non_coding_transcript_exon_variant	Exon 2 of 7	5		ENSP00000455520.1	H3BPY4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438970

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713190

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32888

American (AMR)

AF:

0.00

AC:

AN:

41802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25498

East Asian (EAS)

AF:

0.00

AC:

AN:

38752

South Asian (SAS)

AF:

0.00

AC:

AN:

82582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101268

Other (OTH)

AF:

0.00

AC:

AN:

59390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.0012

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.068

T;.;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.88

L;.;.

PhyloP100

4.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.85

N;.;N

REVEL

Benign

0.11

Sift

Benign

0.22

T;.;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.48

P;.;.

Vest4

0.38

MutPred

0.55

Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);

MVP

0.29

MPC

1.2

ClinPred

0.83

GERP RS

5.9

PromoterAI

0.064

Neutral

(source)

Varity_R

0.24

gMVP

0.26

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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16-75555872-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over