16-75540001-A-C

Position:

• chr16-75540001-A-C

Variant summary

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

The NM_001077418.3(TMEM231):​c.944T>G​(p.Leu315*) 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM231 NM_001077418.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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 0.00736 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/exons	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.944T>G	p.Leu315*	stop_gained	7/7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.1103T>G	p.Leu368*	stop_gained	6/6		NP_001070884.2
TMEM231	NR_074083.2	n.1110T>G		non_coding_transcript_exon_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.944T>G	p.Leu315*	stop_gained	7/7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.1031T>G	p.Leu344*	stop_gained	6/6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.800T>G	p.Leu267*	stop_gained	6/6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.*746T>G		non_coding_transcript_exon_variant	7/7	1		ENSP00000454582.1
TMEM231	ENST00000562410.5	n.*746T>G		3_prime_UTR_variant	7/7	1		ENSP00000454582.1
ENSG00000260092	ENST00000460606.1	n.157+2601T>G		intron_variant		1		ENSP00000457544.1
TMEM231	ENST00000570006.5	n.*324T>G		downstream_gene_variant		5		ENSP00000455520.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000814 AC: 2 AN: 245848 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1458146 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725310

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 26, 2022

Variant summary: TMEM231 c.1103T>G (p.Leu368X) results in a premature termination codon, affecting the last 2 amino acids of the encoded protein. Truncations downstream of this position have not been classified by our laboratory or cited in online databases (ClinVar, HGMD, LOVD). The variant allele was found at a frequency of 8.1e-06 in 245848 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1103T>G in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Benign	0.97
Eigen	Uncertain	0.43
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.77	D
Vest4		0.093
GERP RS		3.8

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: rs756652972; hg19: chr16-75573899;