16-75545825-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_001077418.3(TMEM231):​c.438+1G>T 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 13)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: TMEM231 NM_001077418.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 4 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	NM_001077418.3	MANE Select	c.438+1G>T		splice_donor intron	N/A	NP_001070886.1
	TMEM231	NM_001077416.2		c.597+1G>T		splice_donor intron	N/A	NP_001070884.2
	TMEM231	NR_074083.2		n.604+1G>T		splice_donor intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.438+1G>T		splice_donor intron	N/A	ENSP00000258173.5
	TMEM231	ENST00000568377.5	TSL:1	c.525+1G>T		splice_donor intron	N/A	ENSP00000476267.1
	TMEM231	ENST00000565067.5	TSL:5	c.438+1G>T		splice_donor intron	N/A	ENSP00000457254.1

Frequencies

GnomAD3 genomes Cov.: 13

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1076866 Hom.: 0 Cov.: 15 AF XY: 0.00000187 AC XY: 1 AN XY: 535394

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: 64158

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: 0.00000123 AC: 1 AN: 814630

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

GnomAD4 genome Cov.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.29
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

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;