rs774128939

chr3-122005271-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001199799.2(ILDR1):c.352C>T(p.Arg118Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000454 in 1,562,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (1 hom.)
• Consequence: ILDR1 NM_001199799.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.20

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 3 ACMG points.

• PM1: In a topological_domain Extracellular (size 143) in uniprot entity ILDR1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001199799.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28080943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ILDR1	NM_001199799.2	c.352C>T	p.Arg118Trp	missense_variant	3/8	ENST00000344209.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ILDR1	ENST00000344209.10	c.352C>T	p.Arg118Trp	missense_variant	3/8	1	NM_001199799.2	P2

Frequencies

GnomAD3 genomes AF: 0.0000272 AC: 4 AN: 146818 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000206

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000490

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251062 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000473 AC: 67 AN: 1415544 Hom.: 1 Cov.: 34 AF XY: 0.0000426 AC XY: 30 AN XY: 703818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.24e-7

Gnomad4 OTH exome AF: 0.0000525

GnomAD4 genome AF: 0.0000272 AC: 4 AN: 146818 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 1 AN XY: 71202

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000206

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000490

Alfa AF: 0.0000590 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 118 of the ILDR1 protein (p.Arg118Trp). This variant is present in population databases (rs774128939, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with ILDR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 289899). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 16, 2017

The p.Arg118Trp variant in ILDR1 has not been previously reported in individuals with hearing loss, but has been reported in ClinVar (Variation ID# 289899) as o f uncertain clinical significance. This variant has been identified in 0.2% (53/ 33566) of Latino chromosomes including one homozygote by the Genome Aggregation Database (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs774128939). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conse rvation analysis suggest that the p.Arg118Trp variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Arg118Trp variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.0	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.73
MutPred		0.43		Gain of ubiquitination at K121 (P = 0.0369);Gain of ubiquitination at K121 (P = 0.0369);Gain of ubiquitination at K121 (P = 0.0369);Gain of ubiquitination at K121 (P = 0.0369);
MVP		0.68
MPC		0.29
ClinPred		0.35	T
GERP RS		3.8
Varity_R		0.76
gMVP		0.69

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: rs774128939; hg19: chr3-121724118;