16-75545825-C-T

Variant names:

• chr16-75545825-C-T
• rs1415483600
• NM_001077418.3:c.438+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_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
• Publications: 0 publications found

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

ENSG00000259992 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.13564669 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 VariationId is 437010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.438+1G>A		splice_donor_variant, intron_variant	Intron 3 of 6	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.597+1G>A		splice_donor_variant, intron_variant	Intron 2 of 5		NP_001070884.2
TMEM231	NR_074083.2	n.604+1G>A		splice_donor_variant, intron_variant	Intron 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.438+1G>A		splice_donor_variant, intron_variant	Intron 3 of 6	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.525+1G>A		splice_donor_variant, intron_variant	Intron 2 of 5	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.438+1G>A		splice_donor_variant, intron_variant	Intron 3 of 5	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.*240+1G>A		splice_donor_variant, intron_variant	Intron 3 of 6	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.400+39G>A		intron_variant	Intron 3 of 6	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.00000871 AC: 1 AN: 114782 Hom.: 0 Cov.: 13

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

GnomAD2 exomes AF: 0.0000298 AC: 3 AN: 100746 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000539

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000557 AC: 6 AN: 1076864 Hom.: 0 Cov.: 15 AF XY: 0.00000374 AC XY: 2 AN XY: 535392

African (AFR) AF: 0.00 AC: 0 AN: 24106

American (AMR) AF: 0.00 AC: 0 AN: 27114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19330

East Asian (EAS) AF: 0.00 AC: 0 AN: 33840

South Asian (SAS) AF: 0.00 AC: 0 AN: 64156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3396

European-Non Finnish (NFE) AF: 0.00000614 AC: 5 AN: 814630

Other (OTH) AF: 0.0000214 AC: 1 AN: 46688

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000871 AC: 1 AN: 114782 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 53812

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000344 AC: 1 AN: 29078

American (AMR) AF: 0.00 AC: 0 AN: 10520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2948

East Asian (EAS) AF: 0.00 AC: 0 AN: 4262

South Asian (SAS) AF: 0.00 AC: 0 AN: 2606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 55430

Other (OTH) AF: 0.00 AC: 0 AN: 1456

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000482 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Meckel syndrome, type 11 Pathogenic:1

Jan 06, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Pathogenic:1

Jul 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.1
GERP RS		3.8
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1415483600; hg19: chr16-75579723;