rs3743601

Variant names:

• chr16-75556194-G-A
• rs3743601
• NM_001077418.3:c.16C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-75556194-G-A
• chr16-75556194-G-C

Variant summary

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

The NM_001077418.3(TMEM231):​c.16C>T​(p.Leu6Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000015 in 1,332,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L6V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TMEM231 NM_001077418.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• Publications: 23 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.16C>T	p.Leu6Phe	missense	Exon 1 of 7	NP_001070886.1
	TMEM231	NM_001077416.2		c.78C>T	p.Ser26Ser	synonymous	Exon 1 of 6	NP_001070884.2
	TMEM231	NR_074083.2		n.59C>T		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM231	ENST00000258173.11	TSL:1 MANE Select	c.16C>T	p.Leu6Phe	missense	Exon 1 of 7	ENSP00000258173.5
	TMEM231	ENST00000565067.5	TSL:5	c.16C>T	p.Leu6Phe	missense	Exon 1 of 6	ENSP00000457254.1
	TMEM231	ENST00000568377.5	TSL:1	c.6C>T	p.Ser2Ser	synonymous	Exon 1 of 6	ENSP00000476267.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1332992 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 651880

African (AFR) AF: 0.0000351 AC: 1 AN: 28510

American (AMR) AF: 0.00 AC: 0 AN: 28132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20034

East Asian (EAS) AF: 0.00 AC: 0 AN: 35260

South Asian (SAS) AF: 0.00 AC: 0 AN: 68964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5306

European-Non Finnish (NFE) AF: 9.48e-7 AC: 1 AN: 1054596

Other (OTH) AF: 0.00 AC: 0 AN: 55244

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.44	T
PhyloP100		4.0
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.36
Sift	Benign	0.18	T
Sift4G	Uncertain	0.030	D
Polyphen		0.51	P
Vest4		0.38
MutPred		0.70		Loss of stability (P = 0.0341)
MVP		0.42
ClinPred		0.84	D
GERP RS		4.6
PromoterAI		0.0078	Neutral
Varity_R		0.21
gMVP		0.57
Mutation Taster		=78/22	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: rs3743601; hg19: chr16-75590092;