rs143072070

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001199799.2(ILDR1):c.227C>T(p.Ala76Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000265 in 1,611,892 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

ILDR1
NM_001199799.2 missense, splice_region

Scores

Splicing: ADA: 0.8897

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.64

Publications

1 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011038482).

BP6

Variant 3-122006993-G-A is Benign according to our data. Variant chr3-122006993-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286301.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0015 (228/152204) while in subpopulation AFR AF = 0.00465 (193/41520). AF 95% confidence interval is 0.00411. There are 2 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ILDR1	NM_001199799.2 link	c.227C>T	p.Ala76Val	missense_variant, splice_region_variant	Exon 2 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.227C>T	p.Ala76Val	missense_variant, splice_region_variant	Exon 2 of 8	1	NM_001199799.2	ENSP00000345667.5		Q86SU0-1

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

227

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00464

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

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:

0.0000441

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000400

AC:

100

AN:

249874

AF XY:

0.000356

show subpopulations

Gnomad AFR exome

AF:

0.00503

Gnomad AMR exome

AF:

0.000407

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000136

AC:

199

AN:

1459688

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

726076

show subpopulations

African (AFR)

AF:

0.00395

AC:

132

AN:

33424

American (AMR)

AF:

0.000538

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86056

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.000442

AC:

AN:

4530

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111624

Other (OTH)

AF:

0.000282

AC:

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00150

AC:

228

AN:

152204

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00465

AC:

193

AN:

41520

American (AMR)

AF:

0.00189

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000482

Hom.:

Bravo

AF:

0.00195

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000502

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Splice predictors are inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:2

Jan 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ala76Val in Exon 02 of ILDR1: This variant is not expected to have clinical sign ificance because it has been identified in 0.5% (49/8944) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs143072070). -

Mar 01, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.227C>T (p.A76V) alteration is located in exon 2 (coding exon 2) of the ILDR1 gene. This alteration results from a C to T substitution at nucleotide position 227, causing the alanine (A) at amino acid position 76 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ILDR1-related disorder

Benign:1

Sep 27, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0086

.;T;T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

D;.;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

L;L;L;L

PhyloP100

4.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.2

N;N;.;N

REVEL

Benign

0.18

Sift

Benign

0.16

T;T;.;T

Sift4G

Benign

0.31

T;T;.;T

Polyphen

1.0

D;D;D;D

Vest4

0.41

MVP

0.65

MPC

0.28

ClinPred

0.022

GERP RS

5.6

Varity_R

0.14

gMVP

0.28

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.89

dbscSNV1_RF

Benign

0.67

SpliceAI score (max)

0.070

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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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