3-121994188-G-A

Position:

• chr3-121994188-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_001199799.2(ILDR1):​c.772C>T​(p.Gln258Ter) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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: {Likely_pathogenic=3, Uncertain_significance=2, Pathogenic=3}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ILDR1	NM_001199799.2	c.772C>T	p.Gln258Ter	stop_gained	6/8	ENST00000344209.10	NP_001186728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ILDR1	ENST00000344209.10	c.772C>T	p.Gln258Ter	stop_gained	6/8	1	NM_001199799.2	ENSP00000345667	P2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00540

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000503 AC: 69 AN: 137142 Hom.: 0 AF XY: 0.000456 AC XY: 34 AN XY: 74538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000818

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00598

Gnomad SAS exome AF: 0.0000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000715

GnomAD4 exome AF: 0.000168 AC: 232 AN: 1383784 Hom.: 2 Cov.: 32 AF XY: 0.000179 AC XY: 122 AN XY: 682832

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00574

Gnomad4 SAS exome AF: 0.0000884

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.000225

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74466

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000144 AC: 5

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 42 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2020	- -
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. -
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. -

not provided Pathogenic:1 Uncertain:1

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). -
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) -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
MutationTaster	Benign	1.0	A;A;D;D
Vest4		0.53
GERP RS		4.1

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: rs142746163; hg19: chr3-121713035;