16-75540023-C-A

Variant names:

• chr16-75540023-C-A
• NM_001077418.3:c.922G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001077418.3(TMEM231):​c.922G>T​(p.Gly308*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM231 NM_001077418.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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]

ENSG00000260092 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0305 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.922G>T	p.Gly308*	stop_gained	Exon 7 of 7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.1081G>T	p.Gly361*	stop_gained	Exon 6 of 6		NP_001070884.2
TMEM231	NR_074083.2	n.1088G>T		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.922G>T	p.Gly308*	stop_gained	Exon 7 of 7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.1009G>T	p.Gly337*	stop_gained	Exon 6 of 6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.778G>T	p.Gly260*	stop_gained	Exon 6 of 6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.*724G>T		non_coding_transcript_exon_variant	Exon 7 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.*302G>T		non_coding_transcript_exon_variant	Exon 7 of 7	5		ENSP00000455520.1
TMEM231	ENST00000562410.5	n.*724G>T		3_prime_UTR_variant	Exon 7 of 7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.*302G>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000455520.1
ENSG00000260092	ENST00000460606.1	n.157+2579G>T		intron_variant	Intron 2 of 4	1		ENSP00000457544.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Uncertain:1

Nov 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with TMEM231-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly361*) in the TMEM231 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the TMEM231 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Benign	0.94
Eigen	Benign	0.12
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.28	N
Vest4		0.10
GERP RS		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-75573921;