16-75545335-A-T

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+17T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,603,564 control chromosomes in the GnomAD database, including 52,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5240 hom., cov: 27)
  • Exomes 𝑓: 0.25 (47325 hom.)
• Consequence: TMEM231 NM_001077418.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.851

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-75545335-A-T is Benign according to our data. Variant chr16-75545335-A-T is described in ClinVar as [Benign]. Clinvar id is 257331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75545335-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM231	NM_001077418.3	c.582+17T>A		intron_variant		ENST00000258173.11
TMEM231	NM_001077416.2	c.741+17T>A		intron_variant
TMEM231	NR_074083.2	n.748+17T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM231	ENST00000258173.11	c.582+17T>A		intron_variant		1	NM_001077418.3	P1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39381 AN: 151826 Hom.: 5234 Cov.: 27

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.234

GnomAD3 exomes AF: 0.239 AC: 58635 AN: 245504 Hom.: 7560 AF XY: 0.242 AC XY: 32233 AN XY: 133256

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.201

Gnomad SAS exome AF: 0.235

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.252 AC: 366354 AN: 1451620 Hom.: 47325 Cov.: 32 AF XY: 0.252 AC XY: 181783 AN XY: 720712

Gnomad4 AFR exome AF: 0.286

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.232

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.258

Gnomad4 OTH exome AF: 0.248

GnomAD4 genome AF: 0.259 AC: 39410 AN: 151944 Hom.: 5240 Cov.: 27 AF XY: 0.257 AC XY: 19111 AN XY: 74260

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.236

Alfa AF: 0.178 Hom.: 540

Bravo AF: 0.249

Asia WGS AF: 0.286 AC: 992 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 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 Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.031
Dann	Benign	0.36

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: rs2738801; hg19: chr16-75579233; COSMIC: COSV50737811; COSMIC: COSV50737811;