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: Ambry Genetics, G2P, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001044385.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	NM_001044385.3	MANE Select	c.-12G>A		5_prime_UTR	Exon 1 of 13	NP_001037850.1	Q96Q45-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	ENST00000409883.7	TSL:5 MANE Select	c.-12G>A		5_prime_UTR	Exon 1 of 13	ENSP00000386264.2	Q96Q45-1
	TMEM237	ENST00000286196.9	TSL:5	n.-86G>A		non_coding_transcript_exon	Exon 1 of 12	ENSP00000286196.5	F8WE96
	TMEM237	ENST00000432684.6	TSL:5	n.-12G>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000413230.2	F2Z329

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Joubert syndrome 14 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;