chr3-121993392-G-A

Position:

• chr3-121993392-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001199799.2(ILDR1):​c.1357C>T​(p.Arg453Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ILDR1 NM_001199799.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.477

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-121993391-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.07375461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ILDR1	NM_001199799.2	c.1357C>T	p.Arg453Trp	missense_variant	7/8	ENST00000344209.10	NP_001186728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ILDR1	ENST00000344209.10	c.1357C>T	p.Arg453Trp	missense_variant	7/8	1	NM_001199799.2	ENSP00000345667	P2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000362 AC: 9 AN: 248460 Hom.: 0 AF XY: 0.0000446 AC XY: 6 AN XY: 134612

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1460348 Hom.: 0 Cov.: 40 AF XY: 0.0000179 AC XY: 13 AN XY: 726316

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74360

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2017

The p.Arg453Trp variant in ILDR1 has not been previously reported in individuals with hearing loss. The variant was identified in several populations by the Gen ome Aggregation Database, including 4/30724 South Asian chromosomes (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs376986803); however its frequency is not high enough to rule out a pathogenic role. The arginine (Arg) at position 453 is not conserved in mammals or evolutionarily distant species and 2 mammals (goril la and shrew) carry a tryptophan (Trp), raising the possibility that this change may be tolerated. Additional computational prediction tools suggest that the p. Arg453Trp variant may not impact the protein, though this information is not pre dictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Arg453Trp variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.18	.;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.71	T;.;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.074	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.6	.;M;M;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	D;D;.;D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.0070	D;D;.;D
Polyphen		0.0050	B;B;B;B
Vest4		0.16
MutPred		0.24		.;Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);.;
MVP		0.42
MPC		0.041
ClinPred		0.14	T
GERP RS		-9.6
Varity_R		0.092
gMVP		0.22

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: rs376986803; hg19: chr3-121712239;