2-201621131-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001044385.3(TMEM237):c.*3124A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 152,258 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (17 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: TMEM237 NM_001044385.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 2-201621131-T-A is Benign according to our data. Variant chr2-201621131-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 898803.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0142 (2161/152258) while in subpopulation SAS AF= 0.0268 (129/4822). AF 95% confidence interval is 0.023. There are 17 homozygotes in gnomad4. There are 1151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM237	NM_001044385.3	c.*3124A>T		3_prime_UTR_variant	13/13	ENST00000409883.7
TMEM237	NM_152388.4	c.*3124A>T		3_prime_UTR_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM237	ENST00000409883.7	c.*3124A>T		3_prime_UTR_variant	13/13	5	NM_001044385.3	P4

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2153 AN: 152140 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0322

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0100

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0142 AC: 2161 AN: 152258 Hom.: 17 Cov.: 32 AF XY: 0.0155 AC XY: 1151 AN XY: 74440

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0268

Gnomad4 FIN AF: 0.0322

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.0147 Hom.: 1

Bravo AF: 0.0115

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 14 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.075
Dann	Benign	0.15

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs79378497; hg19: chr2-202485854;