chr3-121993364-C-T

Variant names:

• chr3-121993364-C-T
• rs200630651
• NM_001199799.2:c.1385G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001199799.2(ILDR1):​c.1385G>A​(p.Arg462Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,610,130 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (2 hom.)
• Consequence: ILDR1 NM_001199799.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.459

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03524834).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000177 (27/152304) while in subpopulation EAS AF= 0.00309 (16/5174). AF 95% confidence interval is 0.00194. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ILDR1	NM_001199799.2	c.1385G>A	p.Arg462Gln	missense_variant	Exon 7 of 8	ENST00000344209.10	NP_001186728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ILDR1	ENST00000344209.10	c.1385G>A	p.Arg462Gln	missense_variant	Exon 7 of 8	1	NM_001199799.2	ENSP00000345667.5

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000141 AC: 35 AN: 248530 Hom.: 0 AF XY: 0.000149 AC XY: 20 AN XY: 134580

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000982

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000199 AC: 290 AN: 1457826 Hom.: 2 Cov.: 41 AF XY: 0.000190 AC XY: 138 AN XY: 724418

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00624

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.0000343

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74474

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000665 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 09, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg462Gln variant in ILDR1 has now been identified by our laboratory in th ree individuals with hearing loss, none of whom had a variant affecting the rema ining copy of the gene. This variant has also been identified in 8/64714 Europea n chromosomes and 6/8534 East Asian chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs200630651). Although this var iant has been seen in the general population, its frequency is not high enough t o rule out a pathogenic role. Computational prediction tools and conservation an alyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg462Gln variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0032	.;T;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.62	T;.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.3	.;M;M;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.50	N;N;.;N
REVEL	Benign	0.11
Sift	Uncertain	0.022	D;T;.;D
Sift4G	Uncertain	0.047	D;T;.;D
Polyphen		0.96	D;D;D;D
Vest4		0.24
MVP		0.78
MPC		0.044
ClinPred		0.046	T
GERP RS		0.56
Varity_R		0.051
gMVP		0.25

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: rs200630651; hg19: chr3-121712211; COSMIC: COSV56549024;