NM_001044385.3:c.1065C>G

Variant names:

• chr2-201626120-G-C
• rs149240122
• NM_001044385.3:c.1065C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001044385.3(TMEM237):​c.1065C>G​(p.Leu355Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,610,918 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (12 hom.)
• Consequence: TMEM237 NM_001044385.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.123
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-201626120-G-C is Benign according to our data. Variant chr2-201626120-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212405.
• BP7: Synonymous conserved (PhyloP=-0.123 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00128 (194/151996) while in subpopulation SAS AF = 0.00519 (25/4814). AF 95% confidence interval is 0.00361. There are 0 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.1065C>G	p.Leu355Leu	synonymous	Exon 12 of 13	NP_001037850.1	Q96Q45-1
	TMEM237	NM_152388.4		c.1041C>G	p.Leu347Leu	synonymous	Exon 12 of 13	NP_689601.2	Q96Q45-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM237	ENST00000409883.7	TSL:5 MANE Select	c.1065C>G	p.Leu355Leu	synonymous	Exon 12 of 13	ENSP00000386264.2	Q96Q45-1
	TMEM237	ENST00000621467.5	TSL:1	c.939C>G	p.Leu313Leu	synonymous	Exon 12 of 13	ENSP00000480508.2	A0A087WWU1
	TMEM237	ENST00000409444.6	TSL:5	c.1041C>G	p.Leu347Leu	synonymous	Exon 12 of 13	ENSP00000387203.2	Q96Q45-2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 151878 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00494

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00149

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00165 AC: 405 AN: 244802 AF XY: 0.00195

Gnomad AFR exome AF: 0.000397

Gnomad AMR exome AF: 0.000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00142 AC: 2065 AN: 1458922 Hom.: 12 Cov.: 30 AF XY: 0.00158 AC XY: 1149 AN XY: 725338

African (AFR) AF: 0.000179 AC: 6 AN: 33428

American (AMR) AF: 0.000607 AC: 27 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39666

South Asian (SAS) AF: 0.00480 AC: 410 AN: 85384

European-Finnish (FIN) AF: 0.00385 AC: 205 AN: 53286

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5764

European-Non Finnish (NFE) AF: 0.00119 AC: 1326 AN: 1110556

Other (OTH) AF: 0.00119 AC: 72 AN: 60268

GnomAD4 genome AF: 0.00128 AC: 194 AN: 151996 Hom.: 0 Cov.: 31 AF XY: 0.00140 AC XY: 104 AN XY: 74278

African (AFR) AF: 0.000193 AC: 8 AN: 41468

American (AMR) AF: 0.000393 AC: 6 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4814

European-Finnish (FIN) AF: 0.00494 AC: 52 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00149 AC: 101 AN: 67980

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000974 Hom.: 0

Bravo AF: 0.000797

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.8
DANN	Benign	0.72
PhyloP100		-0.12
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs149240122; hg19: chr2-202490843; COSMIC: COSV105841554; COSMIC: COSV105841554;