rs3743602

Positions:

• chr16-75556215-C-G
• chr16-75556215-C-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.-6G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,416,130 control chromosomes in the GnomAD database, including 40,147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3813 hom., cov: 33)
  • Exomes 𝑓: 0.24 (36334 hom.)
• Consequence: TMEM231 NM_001077418.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.182

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]

TMEM231 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 16-75556215-C-G is Benign according to our data. Variant chr16-75556215-C-G is described in ClinVar as [Benign]. Clinvar id is 257330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-75556215-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	1/7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077418.3	c.-6G>C		5_prime_UTR_variant	1/7	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.57G>C	p.Arg19Arg	synonymous_variant	1/6		NP_001070884.2
TMEM231	NR_074083.2	n.38G>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	1/7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.-16G>C		5_prime_UTR_premature_start_codon_gain_variant	1/6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	1/6	5		ENSP00000457254.1
TMEM231	ENST00000258173.11	c.-6G>C		5_prime_UTR_variant	1/7	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.-16G>C		5_prime_UTR_variant	1/6	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.-6G>C		5_prime_UTR_variant	1/6	5		ENSP00000457254.1
TMEM231	ENST00000562410.5	n.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	1/7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.-6G>C		5_prime_UTR_premature_start_codon_gain_variant	1/7	5		ENSP00000455520.1
TMEM231	ENST00000562410.5	n.-6G>C		non_coding_transcript_exon_variant	1/7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.-6G>C		non_coding_transcript_exon_variant	1/7	5		ENSP00000455520.1
TMEM231	ENST00000562410.5	n.-6G>C		5_prime_UTR_variant	1/7	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.-6G>C		5_prime_UTR_variant	1/7	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33136 AN: 152088 Hom.: 3808 Cov.: 33

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.218 AC: 11887 AN: 54578 Hom.: 1283 AF XY: 0.221 AC XY: 6783 AN XY: 30658

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.241

Gnomad SAS exome AF: 0.179

Gnomad FIN exome AF: 0.280

Gnomad NFE exome AF: 0.244

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.237 AC: 299906 AN: 1263924 Hom.: 36334 Cov.: 32 AF XY: 0.235 AC XY: 144285 AN XY: 613532

Gnomad4 AFR exome AF: 0.162

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.218 AC: 33150 AN: 152206 Hom.: 3813 Cov.: 33 AF XY: 0.217 AC XY: 16129 AN XY: 74408

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.302

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.199

Alfa AF: 0.239 Hom.: 563

Bravo AF: 0.204

Asia WGS AF: 0.238 AC: 825 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.3
DANN	Benign	0.86

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: rs3743602; hg19: chr16-75590113;