rs2540450

chr2-201627272-G-Achr2-201627272-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001044385.3(TMEM237):c.1037+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,319,112 control chromosomes in the GnomAD database, including 69,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7025 hom., cov: 32)
  • Exomes 𝑓: 0.32 (62603 hom.)
• Consequence: TMEM237 NM_001044385.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.472

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=-0.83).
• BP6: Variant 2-201627272-G-A is Benign according to our data. Variant chr2-201627272-G-A is described in ClinVar as [Benign]. Clinvar id is 257314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM237	NM_001044385.3	c.1037+49C>T		intron_variant		ENST00000409883.7
TMEM237	NM_152388.4	c.1013+49C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM237	ENST00000409883.7	c.1037+49C>T		intron_variant		5	NM_001044385.3	P4

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43981 AN: 151928 Hom.: 7023 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.311

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.295

GnomAD3 exomes AF: 0.343 AC: 59191 AN: 172780 Hom.: 11037 AF XY: 0.339 AC XY: 31077 AN XY: 91720

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.302

Gnomad EAS exome AF: 0.623

Gnomad SAS exome AF: 0.339

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.319 AC: 372568 AN: 1167066 Hom.: 62603 Cov.: 15 AF XY: 0.320 AC XY: 187532 AN XY: 586834

Gnomad4 AFR exome AF: 0.178

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.627

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.304

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.289 AC: 44002 AN: 152046 Hom.: 7025 Cov.: 32 AF XY: 0.297 AC XY: 22085 AN XY: 74320

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.311

Gnomad4 EAS AF: 0.628

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.383

Gnomad4 NFE AF: 0.294

Gnomad4 OTH AF: 0.294

Alfa AF: 0.286 Hom.: 7323

Bravo AF: 0.284

Asia WGS AF: 0.446 AC: 1548 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	7.2
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2540450; hg19: chr2-202491995; COSMIC: COSV53803688; COSMIC: COSV53803688;