16-75556194-G-A

Position:

• chr16-75556194-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000258173.11(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 ENST00000258173.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.16C>T	p.Leu6Phe	missense_variant	1/7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.78C>T	p.Ser26=	synonymous_variant	1/6		NP_001070884.2
TMEM231	NR_074083.2	n.59C>T		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.16C>T	p.Leu6Phe	missense_variant	1/7	1	NM_001077418.3	ENSP00000258173	P1

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

Gnomad4 AFR exome AF: 0.0000351

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.48e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	0.15	P;P;P
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.18	T;T
Sift4G	Uncertain	0.030	D;D
Polyphen		0.51	P;.
Vest4		0.38
MutPred		0.70		Loss of stability (P = 0.0341);Loss of stability (P = 0.0341);
MVP		0.42
ClinPred		0.84	D
GERP RS		4.6
Varity_R		0.21
gMVP		0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs3743601; hg19: chr16-75590092;