Genetic Variant TMEM231:p.Leu6Phe (chr16-75556194-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001077418.3(TMEM231):c.16C>T(p.Leu6Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000015 in 1,332,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L6V) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.96

Publications

23 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:

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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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.16C>T	p.Leu6Phe	missense_variant	Exon 1 of 7	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.78C>T	p.Ser26Ser	synonymous_variant	Exon 1 of 6		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.59C>T		non_coding_transcript_exon_variant	Exon 1 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM231	ENST00000258173.11 link	c.16C>T	p.Leu6Phe	missense_variant	Exon 1 of 7	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000565067.5 link	c.16C>T	p.Leu6Phe	missense_variant	Exon 1 of 6	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000568377.5 link	c.6C>T	p.Ser2Ser	synonymous_variant	Exon 1 of 6	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000562410.5 link	n.16C>T		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.16C>T		non_coding_transcript_exon_variant	Exon 1 of 7	5		ENSP00000455520.1	H3BPY4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1332992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

651880

show subpopulations

African (AFR)

AF:

0.0000351

AC:

AN:

28510

American (AMR)

AF:

0.00

AC:

AN:

28132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20034

East Asian (EAS)

AF:

0.00

AC:

AN:

35260

South Asian (SAS)

AF:

0.00

AC:

AN:

68964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5306

European-Non Finnish (NFE)

AF:

9.48e-7

AC:

AN:

1054596

Other (OTH)

AF:

0.00

AC:

AN:

55244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

Alfa

AF:

0.00

Hom.:

1200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.47

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.094

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.44

PhyloP100

4.0

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.18

T;T

Sift4G

Uncertain

0.030

D;D

Polyphen

0.51

P;.

Vest4

0.38

MutPred

0.70

Loss of stability (P = 0.0341);Loss of stability (P = 0.0341);

MVP

0.42

ClinPred

0.84

GERP RS

4.6

PromoterAI

0.0078

Neutral

(source)

Varity_R

0.21

gMVP

0.57

Mutation Taster

=78/22

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over