chr16-75555881-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001077418.3(TMEM231):c.232G>A(p.Asp78Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,441,286 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D78Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 1 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.69

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 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001077418.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20489964).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077418.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM231	NM_001077418.3	MANE Select	c.232G>A	p.Asp78Asn	missense	Exon 2 of 7	NP_001070886.1
TMEM231	NM_001077416.2		c.391G>A	p.Asp131Asn	missense	Exon 1 of 6	NP_001070884.2
TMEM231	NR_074083.2		n.275G>A		non_coding_transcript_exon	Exon 2 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.232G>A	p.Asp78Asn	missense	Exon 2 of 7	ENSP00000258173.5
TMEM231	ENST00000568377.5	TSL:1	c.319G>A	p.Asp107Asn	missense	Exon 1 of 6	ENSP00000476267.1
TMEM231	ENST00000565067.5	TSL:5	c.232G>A	p.Asp78Asn	missense	Exon 2 of 6	ENSP00000457254.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1441286

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

714646

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32914

American (AMR)

AF:

0.00

AC:

AN:

42200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25546

East Asian (EAS)

AF:

0.00

AC:

AN:

38826

South Asian (SAS)

AF:

0.00

AC:

AN:

82970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51290

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102320

Other (OTH)

AF:

0.00

AC:

AN:

59504

Age Distribution

Exome Hom

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.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.099

Eigen

Benign

-0.17

Eigen_PC

Benign

0.0060

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.48

M_CAP

Benign

0.0095

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

6.7

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.050

REVEL

Benign

0.15

Sift

Benign

0.11

Sift4G

Benign

0.69

Polyphen

0.0030

Vest4

0.30

MutPred

0.54

Gain of sheet (P = 0.0221)

MVP

0.23

MPC

0.81

ClinPred

0.90

GERP RS

5.9

PromoterAI

0.011

Neutral

(source)

Varity_R

0.13

gMVP

0.32

Mutation Taster

=86/14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over