chr16-75556024-G-A

Variant names:

• chr16-75556024-G-A
• rs200063331
• ENST00000568377.5:c.176C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001077416.2(TMEM231):​c.248C>T​(p.Ser83Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,417,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S83S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMEM231 NM_001077416.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.080993235).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077416.2. 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.139+47C>T		intron	N/A	NP_001070886.1
	TMEM231	NM_001077416.2		c.248C>T	p.Ser83Leu	missense	Exon 1 of 6	NP_001070884.2
	TMEM231	NR_074083.2		n.182+47C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000568377.5	TSL:1	c.176C>T	p.Ser59Leu	missense	Exon 1 of 6	ENSP00000476267.1
	TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.139+47C>T		intron	N/A	ENSP00000258173.5
	TMEM231	ENST00000565067.5	TSL:5	c.139+47C>T		intron	N/A	ENSP00000457254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1417486 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 700782

African (AFR) AF: 0.0000310 AC: 1 AN: 32248

American (AMR) AF: 0.00 AC: 0 AN: 38226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 37162

South Asian (SAS) AF: 0.00 AC: 0 AN: 81240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1089616

Other (OTH) AF: 0.00 AC: 0 AN: 58576

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.89	T
PhyloP100		-0.023
PrimateAI	Uncertain	0.53	T
Sift4G	Benign	0.13	T
Vest4		0.092
MVP		0.055
MPC		0.78
ClinPred		0.48	T
GERP RS		0.17
PromoterAI		-0.069	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200063331; hg19: chr16-75589922;