rs113186360

chr2-201643412-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001044385.3(TMEM237):c.-12G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,511,066 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 32)
  • Exomes 𝑓: 0.014 (179 hom.)
• Consequence: TMEM237 NM_001044385.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.14

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 2-201643412-C-T is Benign according to our data. Variant chr2-201643412-C-T is described in ClinVar as [Benign]. Clinvar id is 257311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201643412-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0135 (2057/152210) while in subpopulation EAS AF= 0.0421 (217/5154). AF 95% confidence interval is 0.0375. There are 23 homozygotes in gnomad4. There are 1039 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM237	NM_001044385.3	c.-12G>A		5_prime_UTR_variant	1/13	ENST00000409883.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM237	ENST00000409883.7	c.-12G>A		5_prime_UTR_variant	1/13	5	NM_001044385.3	P4
	ENST00000669966.1	n.15C>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2045 AN: 152096 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0163 AC: 1755 AN: 107558 Hom.: 30 AF XY: 0.0179 AC XY: 1067 AN XY: 59558

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.00871

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.0504

Gnomad SAS exome AF: 0.0297

Gnomad FIN exome AF: 0.00611

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0140 AC: 19082 AN: 1358856 Hom.: 179 Cov.: 33 AF XY: 0.0143 AC XY: 9551 AN XY: 669224

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.00859

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.0451

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.00704

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0135 AC: 2057 AN: 152210 Hom.: 23 Cov.: 32 AF XY: 0.0140 AC XY: 1039 AN XY: 74442

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.0421

Gnomad4 SAS AF: 0.0340

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.0236

Alfa AF: 0.0112 Hom.: 1

Bravo AF: 0.0131

Asia WGS AF: 0.0470 AC: 163 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Apr 29, 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 14 Benign:1

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
BayesDel_noAF	Benign	-0.76
Cadd	Benign	3.0
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113186360; hg19: chr2-202508135;