16-75545825-C-T

Position:

chr16-75545825-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_001077418.3(TMEM231):c.438+1G>A variant causes a splice donor, intron change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000087 ( 0 hom., cov: 13)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM231
NM_001077418.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.11

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 links:

ENSG00000259992 (HGNC:):

ENSG00000259992 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13459516 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.5, offset of -38, new splice context is: tcgGTgtgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 16-75545825-C-T is Pathogenic according to our data. Variant chr16-75545825-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 437010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
TMEM231	NM_001077418.3 link	c.438+1G>A	splice_donor_variant, intron_variant	ENST00000258173.11	NP_001070886.1	Q9H6L2-1
TMEM231	NM_001077416.2 link	c.597+1G>A	splice_donor_variant, intron_variant		NP_001070884.2	Q9H6L2
TMEM231	NR_074083.2 link	n.604+1G>A	splice_donor_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
TMEM231	ENST00000258173.11 link	c.438+1G>A	splice_donor_variant, intron_variant	1	NM_001077418.3	ENSP00000258173.5	Q9H6L2-1
TMEM231	ENST00000568377.5 link	c.525+1G>A	splice_donor_variant, intron_variant	1		ENSP00000476267.1	Q9H6L2-2
TMEM231	ENST00000565067.5 link	c.438+1G>A	splice_donor_variant, intron_variant	5		ENSP00000457254.1	H3BTN6
TMEM231	ENST00000562410.5 link	n.*240+1G>A	splice_donor_variant, intron_variant	1		ENSP00000454582.1	H3BMW7
TMEM231	ENST00000570006.5 link	n.400+39G>A	intron_variant	5		ENSP00000455520.1	H3BPY4

Frequencies

GnomAD3 genomes

AF:

0.00000871

AC:

AN:

114782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000344

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000298

AC:

AN:

100746

Hom.:

AF XY:

0.00

AC XY:

AN XY:

52266

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000761

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000539

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000557

AC:

AN:

1076864

Hom.:

Cov.:

AF XY:

0.00000374

AC XY:

AN XY:

535392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000614

Gnomad4 OTH exome

AF:

0.0000214

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000871

AC:

AN:

114782

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

53812

show subpopulations

Gnomad4 AFR

AF:

0.0000344

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000482

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel syndrome, type 11

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 06, 2016

- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 04, 2024

This sequence change affects a donor splice site in intron 2 of the TMEM231 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMEM231 are known to be pathogenic (PMID: 23012439, 23349226). This variant is present in population databases (no rsID available, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with clinical features of Joubert syndrome (PMID: 32055034, 32386258). ClinVar contains an entry for this variant (Variation ID: 437010). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

GERP RS

3.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.97

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.97

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over