rs73989521

chr2-201626089-C-Achr2-201626089-C-G

Variant summary

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

The NM_001044385.3(TMEM237):c.1096G>T(p.Ala366Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0518 in 1,608,098 control chromosomes in the GnomAD database, including 2,715 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (649 hom., cov: 31)
  • Exomes 𝑓: 0.049 (2066 hom.)
• Consequence: TMEM237 NM_001044385.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.766

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018060207).
• BP6: Variant 2-201626089-C-A is Benign according to our data. Variant chr2-201626089-C-A is described in ClinVar as [Benign]. Clinvar id is 130592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201626089-C-A is described in Lovd as [Benign]. Variant chr2-201626089-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM237	NM_001044385.3	c.1096G>T	p.Ala366Ser	missense_variant	12/13	ENST00000409883.7
TMEM237	NM_152388.4	c.1072G>T	p.Ala358Ser	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM237	ENST00000409883.7	c.1096G>T	p.Ala366Ser	missense_variant	12/13	5	NM_001044385.3	P4

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11444 AN: 151746 Hom.: 649 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0555

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.0163

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0689

GnomAD3 exomes AF: 0.0444 AC: 10726 AN: 241314 Hom.: 370 AF XY: 0.0434 AC XY: 5664 AN XY: 130574

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.0319

Gnomad ASJ exome AF: 0.0501

Gnomad EAS exome AF: 0.000228

Gnomad SAS exome AF: 0.0159

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0493 AC: 71782 AN: 1456234 Hom.: 2066 Cov.: 31 AF XY: 0.0482 AC XY: 34901 AN XY: 723718

Gnomad4 AFR exome AF: 0.155

Gnomad4 AMR exome AF: 0.0344

Gnomad4 ASJ exome AF: 0.0495

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.0173

Gnomad4 NFE exome AF: 0.0524

Gnomad4 OTH exome AF: 0.0497

GnomAD4 genome AF: 0.0754 AC: 11450 AN: 151864 Hom.: 649 Cov.: 31 AF XY: 0.0721 AC XY: 5349 AN XY: 74216

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0554

Gnomad4 ASJ AF: 0.0496

Gnomad4 EAS AF: 0.000969

Gnomad4 SAS AF: 0.0163

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.0546

Gnomad4 OTH AF: 0.0682

Alfa AF: 0.0594 Hom.: 376

Bravo AF: 0.0821

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0579 AC: 223

ESP6500AA AF: 0.149 AC: 546

ESP6500EA AF: 0.0537 AC: 439

ExAC AF: 0.0461 AC: 5570

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Jan 30, 2014	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 14 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	18
Dann	Benign	0.97
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.0018	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.032
Sift	Benign	0.22	T;T;.
Sift4G	Benign	0.24	T;T;T
Vest4		0.084
MPC		0.050
ClinPred		0.0047	T
GERP RS		2.0
Varity_R		0.040
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs73989521; hg19: chr2-202490812;