rs142746163
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 9P and 5B. PVS1PP5BS1_SupportingBS2
The NM_001199799.2(ILDR1):c.772C>T(p.Gln258*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000175 in 1,536,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00017 ( 2 hom. )
Consequence
ILDR1
NM_001199799.2 stop_gained
NM_001199799.2 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 6.34
Genes affected
ILDR1 (HGNC:28741): (immunoglobulin like domain containing receptor 1) This gene encodes a protein that contains an immunoglobulin-like domain. The encoded protein may function as a multimeric receptor at the cell surface. The expression of this gene may be a diagnostic marker for cancer progression. Alternatively spliced transcript variants encoding multiple protein isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 3-121994188-G-A is Pathogenic according to our data. Variant chr3-121994188-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228748.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=3}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000243 (37/152316) while in subpopulation EAS AF= 0.00541 (28/5176). AF 95% confidence interval is 0.00384. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000243 AC: 37AN: 152198Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000503 AC: 69AN: 137142Hom.: 0 AF XY: 0.000456 AC XY: 34AN XY: 74538
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GnomAD4 exome AF: 0.000168 AC: 232AN: 1383784Hom.: 2 Cov.: 32 AF XY: 0.000179 AC XY: 122AN XY: 682832
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GnomAD4 genome 0.000243 AC: 37AN: 152316Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 42 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000469, PM2_M). The variant has been reported to be associated with ILDR1 related disorder (ClinVar ID: VCV000228748, PMID:27610647, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2024 | Variant summary: ILDR1 c.772C>T (p.Gln258X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0005 in 137142 control chromosomes, predominantly at a frequency of 0.006 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ILDR1 causing Autosomal Recessive Nonsyndromic Hearing Loss 42 phenotype. However, c.772C>T has been reported in the literature in individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 42 (e.g. Chen_2016). These data indicate that the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 27610647). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 228748). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 01, 2020 | - - |
not provided Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2024 | Reported in a patient with hearing loss in published literature; clinical information is limited (PMID: 27610647); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31345219, 31980526, 37435641, 27610647) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 08, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 228748). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 27610647). This variant is present in population databases (rs142746163, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This sequence change creates a premature translational stop signal (p.Gln258*) in the ILDR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ILDR1 are known to be pathogenic (PMID: 21255762). - |
Hearing impairment Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PVS1_Strong, PM2_Supporting - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 2016 | The p.Gln258X variant in ILDR1 (NM_001199799.1) has now been identified by our l aboratory in two individuals with hearing loss, one of whom had an alternate gen etic cause of their hearing loss identified. This variant has also been identifi ed in 1/206 of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142746163). Although this variant has b een seen in the general population, its frequency is not high enough to rule out a pathogenic role. This nonsense variant leads to a premature termination codon at position 258 in exon 6 of the ILDR1 NM_001199799.1 transcript isoform. Howev er, in an alternate isoform of ILDR1 (NM_175924.3), the variant occurs in an int ronic region (c.647-218C>T in intron 5) and is not predicted to have an impact o n that protein isoform. While loss of function variants in ILDR1 have been shown to cause hearing loss, none have been reported in exon 6 of the NM_001199799.1 ILDR1 transcript to date. Therefore, it is unclear whether loss of function vari ants in exon 6 of this transcript isoform can lead to hearing loss, or only thos e affecting coding regions of the NM_175924.3 transcript isoform are causative f or disease. In summary, the clinical significance of the p.Gln258X variant in th e NM_001199799.1 transcript of ILDR1 is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at