rs113186360

Variant names:

• chr2-201643412-C-T
• rs113186360
• NM_001044385.3:c.-12G>A

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -2.14
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Joubert syndrome 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with renal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287133 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM237	NM_001044385.3	c.-12G>A		5_prime_UTR_variant	Exon 1 of 13	ENST00000409883.7	NP_001037850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM237	ENST00000409883.7	c.-12G>A		5_prime_UTR_variant	Exon 1 of 13	5	NM_001044385.3	ENSP00000386264.2

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

GnomAD2 exomes AF: 0.0163 AC: 1755 AN: 107558 AF XY: 0.0179

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 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

African (AFR) AF: 0.0113 AC: 317 AN: 27998

American (AMR) AF: 0.00859 AC: 272 AN: 31662

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 399 AN: 24058

East Asian (EAS) AF: 0.0451 AC: 1385 AN: 30690

South Asian (SAS) AF: 0.0281 AC: 2129 AN: 75752

European-Finnish (FIN) AF: 0.00704 AC: 325 AN: 46156

Middle Eastern (MID) AF: 0.0191 AC: 100 AN: 5238

European-Non Finnish (NFE) AF: 0.0125 AC: 13303 AN: 1060984

Other (OTH) AF: 0.0151 AC: 852 AN: 56318

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

African (AFR) AF: 0.0118 AC: 489 AN: 41556

American (AMR) AF: 0.0114 AC: 175 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3466

East Asian (EAS) AF: 0.0421 AC: 217 AN: 5154

South Asian (SAS) AF: 0.0340 AC: 164 AN: 4824

European-Finnish (FIN) AF: 0.00546 AC: 58 AN: 10614

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0124 AC: 840 AN: 67978

Other (OTH) AF: 0.0236 AC: 50 AN: 2116

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Joubert syndrome 14 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-2.1
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs113186360; hg19: chr2-202508135; COSMIC: COSV107261805; COSMIC: COSV107261805;