rs77570029

Positions:

• chr2-201626051-A-G

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.1134T>C​(p.Tyr378=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,596,412 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (3 hom.)
• Consequence: TMEM237 NM_001044385.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.313

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-201626051-A-G is Benign according to our data. Variant chr2-201626051-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00193 (294/152226) while in subpopulation AFR AF= 0.00655 (272/41522). AF 95% confidence interval is 0.00591. There are 1 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM237	NM_001044385.3	c.1134T>C	p.Tyr378=	synonymous_variant	12/13	ENST00000409883.7
TMEM237	NM_152388.4	c.1110T>C	p.Tyr370=	synonymous_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM237	ENST00000409883.7	c.1134T>C	p.Tyr378=	synonymous_variant	12/13	5	NM_001044385.3	P4

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152108 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000468 AC: 104 AN: 222278 Hom.: 0 AF XY: 0.000376 AC XY: 45 AN XY: 119758

Gnomad AFR exome AF: 0.00629

Gnomad AMR exome AF: 0.000573

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000197 AC: 284 AN: 1444186 Hom.: 3 Cov.: 30 AF XY: 0.000184 AC XY: 132 AN XY: 716568

Gnomad4 AFR exome AF: 0.00567

Gnomad4 AMR exome AF: 0.000572

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000453

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152226 Hom.: 1 Cov.: 31 AF XY: 0.00180 AC XY: 134 AN XY: 74424

Gnomad4 AFR AF: 0.00655

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00229

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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	Eurofins Ntd Llc (ga)	Jul 02, 2015	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 30, 2018

- -

Joubert syndrome 14 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.060
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs77570029; hg19: chr2-202490774;