16-75540025-C-G

Variant names:

• chr16-75540025-C-G
• rs746970206
• NM_001077418.3:c.920G>C

Variant summary

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

The NM_001077418.3(TMEM231):​c.920G>C​(p.Arg307Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R307Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.891
• 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: 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

ENSG00000260092 (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=0.08118209).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	NM_001077418.3	MANE Select	c.920G>C	p.Arg307Pro	missense	Exon 7 of 7	NP_001070886.1	Q9H6L2-1
	TMEM231	NM_001077416.2		c.1079G>C	p.Arg360Pro	missense	Exon 6 of 6	NP_001070884.2	Q9H6L2
	TMEM231	NR_074083.2		n.1086G>C		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.920G>C	p.Arg307Pro	missense	Exon 7 of 7	ENSP00000258173.5	Q9H6L2-1
	TMEM231	ENST00000568377.5	TSL:1	c.1007G>C	p.Arg336Pro	missense	Exon 6 of 6	ENSP00000476267.1	Q9H6L2-2
	TMEM231	ENST00000565067.5	TSL:5	c.776G>C	p.Arg259Pro	missense	Exon 6 of 6	ENSP00000457254.1	H3BTN6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.18
DANN	Benign	0.61
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		-0.89
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.086
Sift	Benign	0.14	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.59		Gain of catalytic residue at P306 (P = 0.0113)
MVP		0.048
MPC		0.0075
ClinPred		0.043	T
GERP RS		-3.9
Varity_R		0.13
gMVP		0.45
Mutation Taster		=92/8	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: rs746970206; hg19: chr16-75573923;