rs149240122

Positions:

• chr2-201626120-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001044385.3(TMEM237):​c.1065C>G​(p.Leu355Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,610,918 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (12 hom.)
• Consequence: TMEM237 NM_001044385.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.123

Genes affected

TMEM237 (HGNC:14432): (transmembrane protein 237) The protein encoded by this gene is a tetraspanin protein that is thought to be involved in WNT signaling. Defects in this gene are a cause of Joubert syndrome-14. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

TMEM237 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-201626120-G-C is Benign according to our data. Variant chr2-201626120-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212405.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=1}. Variant chr2-201626120-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.123 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00128 (194/151996) while in subpopulation SAS AF= 0.00519 (25/4814). AF 95% confidence interval is 0.00361. There are 0 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM237	NM_001044385.3	c.1065C>G	p.Leu355Leu	synonymous_variant	12/13	ENST00000409883.7	NP_001037850.1
TMEM237	NM_152388.4	c.1041C>G	p.Leu347Leu	synonymous_variant	12/13		NP_689601.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM237	ENST00000409883.7	c.1065C>G	p.Leu355Leu	synonymous_variant	12/13	5	NM_001044385.3	ENSP00000386264.2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 151878 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00494

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00165 AC: 405 AN: 244802 Hom.: 4 AF XY: 0.00195 AC XY: 259 AN XY: 132522

Gnomad AFR exome AF: 0.000397

Gnomad AMR exome AF: 0.000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00476

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00142 AC: 2065 AN: 1458922 Hom.: 12 Cov.: 30 AF XY: 0.00158 AC XY: 1149 AN XY: 725338

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000607

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00480

Gnomad4 FIN exome AF: 0.00385

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00128 AC: 194 AN: 151996 Hom.: 0 Cov.: 31 AF XY: 0.00140 AC XY: 104 AN XY: 74278

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00494

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000974 Hom.: 0

Bravo AF: 0.000797

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 25, 2015	- -

Joubert syndrome 14 Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TMEM237: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.8
DANN	Benign	0.72

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

LitVar

Other links and lift over

dbSNP: rs149240122; hg19: chr2-202490843; COSMIC: COSV105841554; COSMIC: COSV105841554;