NM_001199799.2:c.25C>T

Variant names:

• chr3-122022053-G-A
• rs1217446345
• NM_001199799.2:c.25C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001199799.2(ILDR1):​c.25C>T​(p.Pro9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ILDR1 NM_001199799.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.555
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11842832).
• BP6: Variant 3-122022053-G-A is Benign according to our data. Variant chr3-122022053-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 517153.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ILDR1	NM_001199799.2	c.25C>T	p.Pro9Ser	missense_variant	Exon 1 of 8	ENST00000344209.10	NP_001186728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ILDR1	ENST00000344209.10	c.25C>T	p.Pro9Ser	missense_variant	Exon 1 of 8	1	NM_001199799.2	ENSP00000345667.5
ILDR1	ENST00000273691.7	c.25C>T	p.Pro9Ser	missense_variant	Exon 1 of 7	1		ENSP00000273691.3
ILDR1	ENST00000393631.5	c.25C>T	p.Pro9Ser	missense_variant	Exon 1 of 6	1		ENSP00000377251.1
ILDR1	ENST00000642615.1	n.25C>T		non_coding_transcript_exon_variant	Exon 1 of 8			ENSP00000495499.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000829 AC: 2 AN: 241158 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459026 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 725498

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110864

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 23, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Pro9Ser in exon 1 of ILDR1: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, 3 mammals (squirrel, jerboa, and Weddell seal) have a serine (Ser) at this po sition despite high nearby amino acid conservation. In addition, computational p rediction tools do not suggest a high likelihood of impact to the protein. It ha s also been identified in 2/106558 European chromosomes by the genome Aggregatio n Database (gnomAD , http://gnomad.broadinstitute.org/). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0017	.;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.63	T;.;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;N;N;N
PhyloP100		0.56
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.31	N;N;.;N
REVEL	Benign	0.046
Sift	Benign	0.036	D;T;.;T
Sift4G	Benign	0.14	T;T;.;T
Polyphen		0.073	B;B;B;B
Vest4		0.16
MutPred		0.42		Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);
MVP		0.72
MPC		0.040
ClinPred		0.080	T
GERP RS		3.6
PromoterAI		0.020	Neutral
Varity_R		0.032
gMVP		0.64
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1217446345; hg19: chr3-121740900;