rs760426025

Variant names:

• chr16-75542598-T-C
• rs760426025
• NM_001077418.3:c.664+4A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001077418.3(TMEM231):​c.664+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000483 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: TMEM231 NM_001077418.3 splice_region, intron
• Scores: Splicing: ADA: 0.9819
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 3.93

Genes affected

TMEM231 (HGNC:37234): (transmembrane protein 231) This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

ENSG00000260092 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• PP5: Variant 16-75542598-T-C is Pathogenic according to our data. Variant chr16-75542598-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437009.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM231	NM_001077418.3	c.664+4A>G		splice_region_variant, intron_variant	Intron 5 of 6	ENST00000258173.11	NP_001070886.1
TMEM231	NM_001077416.2	c.823+4A>G		splice_region_variant, intron_variant	Intron 4 of 5		NP_001070884.2
TMEM231	NR_074083.2	n.830+4A>G		splice_region_variant, intron_variant	Intron 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM231	ENST00000258173.11	c.664+4A>G		splice_region_variant, intron_variant	Intron 5 of 6	1	NM_001077418.3	ENSP00000258173.5
TMEM231	ENST00000568377.5	c.751+4A>G		splice_region_variant, intron_variant	Intron 4 of 5	1		ENSP00000476267.1
TMEM231	ENST00000565067.5	c.520+4A>G		splice_region_variant, intron_variant	Intron 4 of 5	5		ENSP00000457254.1
ENSG00000260092	ENST00000460606.1	n.157+4A>G		splice_region_variant, intron_variant	Intron 2 of 4	1		ENSP00000457544.1
TMEM231	ENST00000562410.5	n.*466+4A>G		splice_region_variant, intron_variant	Intron 5 of 6	1		ENSP00000454582.1
TMEM231	ENST00000570006.5	n.*44+4A>G		splice_region_variant, intron_variant	Intron 5 of 6	5		ENSP00000455520.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000682 AC: 17 AN: 249240 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135218

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461396 Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 34 AN XY: 727006

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Meckel syndrome, type 11 Pathogenic:1

Jan 08, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Pathogenic:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 of the TMEM231 gene. It does not directly change the encoded amino acid sequence of the TMEM231 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs760426025, gnomAD 0.02%). This variant has been observed in individual(s) with Meckel syndrome (PMID: 25869670). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 437009). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in altered splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 25869670). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Aug 24, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome and related disorders Pathogenic:1

Dec 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TMEM231 c.823+4A>G, also referred to as c.664+4A>G, alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing and results in a frameshift leading to a premature truncation that is expected to undergo nonsense mediated decay (Roberson_2015). The variant allele was found at a frequency of 6.8e-05 in 249240 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TMEM231 causing Joubert Syndrome And Related Disorders (6.8e-05 vs 0.0004), allowing no conclusion about variant significance. c.823+4A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Meckel Syndrome from several different families (Roberson_2015). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 25869670). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

TMEM231-related disorder Pathogenic:1

Jul 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TMEM231 c.823+4A>G variant is predicted to interfere with splicing. This variant was reported in individual with Meckel syndrome (Roberson et al 2015. PubMed ID: 25869670) and in an individual with inherited retinal disease (Supplementary table 1; Weisschuh et al 2024. PubMed ID: 37734845). On an alternate transcript of the gene, this variant is referred to as c.664+4A>G ( NM_001077418). This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751); splicing variants in TMEM231 are expected to be pathogenic. This variant is reported in 0.019% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic. -

Joubert syndrome 20 Uncertain:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: -43
DS_DL_spliceai		0.81		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs760426025; hg19: chr16-75576496;