Genetic Variant TMEM231:p.Val222Ile (chr16-75542602-C-T) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3PM2PP3PP5_Very_Strong

The NM_001077418.3(TMEM231):c.664G>A(p.Val222Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004570099: Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID:23349226).; SCV004737036: Functional studies found that this variant interferes with normal splicing (Shaheen et al. 2013. PubMed ID: 23349226; Maddirevula et al. 2020. PubMed ID: 32552793, Table S1).; SCV005871267: PS3, PP3 no". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V222F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TMEM231
NM_001077418.3 missense, splice_region

Scores

Splicing: ADA: 0.9936

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 2.20

Publications

5 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Meckel syndrome, type 11
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
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: Pathogenic. The variant received 15 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004570099: Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 23349226).; SCV004737036: Functional studies found that this variant interferes with normal splicing (Shaheen et al. 2013. PubMed ID: 23349226; Maddirevula et al. 2020. PubMed ID: 32552793, Table S1).; SCV005871267: PS3, PP3 no

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-75542602-C-T is Pathogenic according to our data. Variant chr16-75542602-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 64619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	UniProt
TMEM231	NM_001077418.3	MANE Select	c.664G>A	p.Val222Ile	missense splice_region	Exon 5 of 7	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2		c.823G>A	p.Val275Ile	missense splice_region	Exon 4 of 6	NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2		n.830G>A		splice_region non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.664G>A	p.Val222Ile	missense splice_region	Exon 5 of 7	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5	TSL:1	c.751G>A	p.Val251Ile	missense splice_region	Exon 4 of 6	ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5	TSL:5	c.520G>A	p.Val174Ile	missense splice_region	Exon 4 of 6	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249246

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461414

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111646

Other (OTH)

AF:

0.00

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

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

AF:

0.0000395

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41410

American (AMR)

AF:

0.0000656

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000712

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000827

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 (2)

Meckel syndrome, type 11 (2)

TMEM231-related disorder (2)

Joubert syndrome 20 (1)

Meckel-Gruber syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.078

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.89

PhyloP100

2.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.28

REVEL

Benign

0.11

Sift

Benign

0.30

Sift4G

Benign

0.40

Polyphen

0.018

Vest4

0.14

MutPred

0.68

Loss of catalytic residue at V222 (P = 0.0071)

MVP

0.12

MPC

0.012

ClinPred

0.34

GERP RS

3.4

Varity_R

0.042

gMVP

0.29

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.86

SpliceAI score (max)

0.84

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.50

Position offset: -47

DS_DL_spliceai

0.84

Position offset: 0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over