rs114290622

Positions:

• chr16-75545349-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001077418.3(TMEM231):​c.582+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,612,598 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (60 hom., cov: 22)
  • Exomes 𝑓: 0.0017 (63 hom.)
• Consequence: TMEM231 NM_001077418.3 splice_region, intron
• Scores: Splicing: ADA: 0.1897
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.22

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-75545349-T-C is Benign according to our data. Variant chr16-75545349-T-C is described in ClinVar as [Benign]. Clinvar id is 130589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75545349-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.582+3A>G		splice_region_variant, intron_variant		ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.741+3A>G		splice_region_variant, intron_variant			NP_001070884.2
TMEM231	NR_074083.2	n.748+3A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.582+3A>G		splice_region_variant, intron_variant		1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.669+3A>G		splice_region_variant, intron_variant		1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.438+477A>G		intron_variant		5		ENSP00000457254.1
ENSG00000260092	ENST00000460606.1	n.75+3A>G		splice_region_variant, intron_variant		1		ENSP00000457544.1
TMEM231	ENST00000562410.5	n.*384+3A>G		splice_region_variant, intron_variant		1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.544+3A>G		splice_region_variant, intron_variant		5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2521 AN: 152108 Hom.: 58 Cov.: 22

Gnomad AFR AF: 0.0578

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00415 AC: 1031 AN: 248492 Hom.: 25 AF XY: 0.00299 AC XY: 403 AN XY: 134784

Gnomad AFR exome AF: 0.0573

Gnomad AMR exome AF: 0.00314

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00166 AC: 2417 AN: 1460372 Hom.: 63 Cov.: 31 AF XY: 0.00138 AC XY: 1003 AN XY: 726248

Gnomad4 AFR exome AF: 0.0566

Gnomad4 AMR exome AF: 0.00354

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000774

Gnomad4 OTH exome AF: 0.00423

GnomAD4 genome AF: 0.0167 AC: 2544 AN: 152226 Hom.: 60 Cov.: 22 AF XY: 0.0162 AC XY: 1205 AN XY: 74418

Gnomad4 AFR AF: 0.0582

Gnomad4 AMR AF: 0.00661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00785 Hom.: 10

Bravo AF: 0.0187

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	10
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs114290622; hg19: chr16-75579247;