3-121993155-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.27

Publications

3 publications found

Variant links:

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]

ILDR1 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 42
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ILDR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041682333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ILDR1	NM_001199799.2 link	c.1594C>T	p.Arg532Cys	missense_variant	Exon 7 of 8	ENST00000344209.10	NP_001186728.1	Q86SU0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ILDR1	ENST00000344209.10 link	c.1594C>T	p.Arg532Cys	missense_variant	Exon 7 of 8	1	NM_001199799.2	ENSP00000345667.5		Q86SU0-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000109

AC:

AN:

210596

AF XY:

0.000123

show subpopulations

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 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.:

Cov.:

AF XY:

0.000140

AC XY:

100

AN XY:

713552

show subpopulations

African (AFR)

AF:

0.0000606

AC:

AN:

33018

American (AMR)

AF:

0.000121

AC:

AN:

41396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25726

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38442

South Asian (SAS)

AF:

0.000121

AC:

AN:

82932

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51794

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000165

AC:

181

AN:

1099996

Other (OTH)

AF:

0.000118

AC:

AN:

59526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000105

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41526

American (AMR)

AF:

0.000392

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

67928

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000183

Hom.:

Bravo

AF:

0.000246

ExAC

AF:

0.000116

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 25, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Inborn genetic diseases

Uncertain:1

Nov 19, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.13

.;T;T;.

Eigen

Benign

-0.027

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.77

T;.;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.042

T;T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.7

.;M;M;.

PhyloP100

2.3

PrimateAI

Benign

0.29

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

GERP RS

4.9

Varity_R

0.18

gMVP

0.15

Mutation Taster

=76/24

polymorphism

(source)

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

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3-121993155-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over