3-121993155-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001199799.2(ILDR1):c.1594C>T(p.Arg532Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,590,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ILDR1 NM_001199799.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.27

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041682333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ILDR1	NM_001199799.2	c.1594C>T	p.Arg532Cys	missense_variant	7/8	ENST00000344209.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ILDR1	ENST00000344209.10	c.1594C>T	p.Arg532Cys	missense_variant	7/8	1	NM_001199799.2	P2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152036 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000393

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 23 AN: 210596 Hom.: 0 AF XY: 0.000123 AC XY: 14 AN XY: 113480

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0000551

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000373

GnomAD4 exome AF: 0.000146 AC: 210 AN: 1438574 Hom.: 0 Cov.: 30 AF XY: 0.000140 AC XY: 100 AN XY: 713552

Gnomad4 AFR exome AF: 0.0000606

Gnomad4 AMR exome AF: 0.000121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.000121

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.000165

Gnomad4 OTH exome AF: 0.000118

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.000246

ExAC AF: 0.000116 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 532 of the ILDR1 protein (p.Arg532Cys). This variant is present in population databases (rs201511787, gnomAD 0.01%). 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: 1315006). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	GeneDx	Oct 25, 2021	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 -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.1594C>T (p.R532C) alteration is located in exon 7 (coding exon 7) of the ILDR1 gene. This alteration results from a C to T substitution at nucleotide position 1594, causing the arginine (R) at amino acid position 532 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Benign	-0.027
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.77	T;.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.042	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.2	D;D;.;D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Benign	0.074	T;T;.;D
Polyphen		0.027	B;B;B;B
Vest4		0.27
MVP		0.81
MPC		0.32
ClinPred		0.32	T
GERP RS		4.9
Varity_R		0.18
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs201511787; hg19: chr3-121712002;