rs6736435

Variant names:

• chr2-201643392-A-C
• rs6736435
• NM_001044385.3:c.9T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-201643392-A-C
• chr2-201643392-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001044385.3(TMEM237):​c.9T>G​(p.Thr3Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,544,272 control chromosomes in the GnomAD database, including 999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (159 hom., cov: 32)
  • Exomes 𝑓: 0.012 (840 hom.)
• Consequence: TMEM237 NM_001044385.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.219
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 2-201643392-A-C is Benign according to our data. Variant chr2-201643392-A-C is described in ClinVar as Benign. ClinVar VariationId is 130594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.219 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

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.9T>G	p.Thr3Thr	synonymous	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.9T>G	p.Thr3Thr	synonymous	Exon 1 of 13	ENSP00000386264.2	Q96Q45-1
	TMEM237	ENST00000286196.9	TSL:5	n.-66T>G		non_coding_transcript_exon	Exon 1 of 12	ENSP00000286196.5	F8WE96
	TMEM237	ENST00000432684.6	TSL:5	n.9T>G		non_coding_transcript_exon	Exon 1 of 10	ENSP00000413230.2	F2Z329

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3924 AN: 151634 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.00308

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.0249 AC: 3450 AN: 138466 AF XY: 0.0265

Gnomad AFR exome AF: 0.0464

Gnomad AMR exome AF: 0.00401

Gnomad ASJ exome AF: 0.00322

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0119 AC: 16565 AN: 1392530 Hom.: 840 Cov.: 33 AF XY: 0.0131 AC XY: 8981 AN XY: 686874

African (AFR) AF: 0.0540 AC: 1671 AN: 30932

American (AMR) AF: 0.00508 AC: 180 AN: 35428

Ashkenazi Jewish (ASJ) AF: 0.00336 AC: 84 AN: 25018

East Asian (EAS) AF: 0.178 AC: 6195 AN: 34720

South Asian (SAS) AF: 0.0542 AC: 4271 AN: 78786

European-Finnish (FIN) AF: 0.0113 AC: 536 AN: 47556

Middle Eastern (MID) AF: 0.0261 AC: 146 AN: 5588

European-Non Finnish (NFE) AF: 0.00215 AC: 2313 AN: 1076736

Other (OTH) AF: 0.0202 AC: 1169 AN: 57766

GnomAD4 genome AF: 0.0260 AC: 3938 AN: 151742 Hom.: 159 Cov.: 32 AF XY: 0.0272 AC XY: 2018 AN XY: 74166

African (AFR) AF: 0.0535 AC: 2214 AN: 41356

American (AMR) AF: 0.00969 AC: 148 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.176 AC: 897 AN: 5108

South Asian (SAS) AF: 0.0549 AC: 263 AN: 4794

European-Finnish (FIN) AF: 0.0140 AC: 147 AN: 10528

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00308 AC: 209 AN: 67900

Other (OTH) AF: 0.0185 AC: 39 AN: 2108

Alfa AF: 0.00802 Hom.: 8

Bravo AF: 0.0273

Asia WGS AF: 0.106 AC: 368 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Joubert syndrome 14 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.4
DANN	Benign	0.58
PhyloP100		-0.22
PromoterAI		-0.010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6736435; hg19: chr2-202508115; COSMIC: COSV53804189; COSMIC: COSV53804189;