rs143072070

chr3-122006993-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

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. 14/23 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:2 B:3
• Conservation: PhyloP100: 4.64

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 Benign. Variant got -7 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
• 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 id is 286301.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2, Benign=1}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ILDR1	NM_001199799.2	c.227C>T	p.Ala76Val	missense_variant, splice_region_variant	2/8	ENST00000344209.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ILDR1	ENST00000344209.10	c.227C>T	p.Ala76Val	missense_variant, splice_region_variant	2/8	1	NM_001199799.2	P2

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152086 Hom.: 2 Cov.: 32

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

GnomAD3 exomes AF: 0.000400 AC: 100 AN: 249874 Hom.: 0 AF XY: 0.000356 AC XY: 48 AN XY: 135016

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 SAS 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.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 99 AN XY: 726076

Gnomad4 AFR exome AF: 0.00395

Gnomad4 AMR exome AF: 0.000538

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152204 Hom.: 2 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74418

Gnomad4 AFR AF: 0.00465

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000259 Hom.: 1

Bravo AF: 0.00195

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000502 AC: 61

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 28, 2017	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). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2016	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	27
Dann	Benign	0.97
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
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	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs143072070; hg19: chr3-121725840; COSMIC: COSV56555104;