chr3-121993590-A-G

Position:

• chr3-121993590-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001199799.2(ILDR1):​c.1159T>C​(p.Ser387Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,614,122 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (3 hom.)
• Consequence: ILDR1 NM_001199799.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0200

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009766668).
• BP6: Variant 3-121993590-A-G is Benign according to our data. Variant chr3-121993590-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178382.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr3-121993590-A-G is described in Lovd as [Likely_benign]. Variant chr3-121993590-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000317 (464/1461892) while in subpopulation MID AF= 0.00884 (51/5768). AF 95% confidence interval is 0.00691. There are 3 homozygotes in gnomad4_exome. There are 284 alleles in male gnomad4_exome subpopulation. Median coverage is 41. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ILDR1	NM_001199799.2	c.1159T>C	p.Ser387Pro	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.1159T>C	p.Ser387Pro	missense_variant	7/8	1	NM_001199799.2	ENSP00000345667.5

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000477 AC: 120 AN: 251480 Hom.: 0 AF XY: 0.000537 AC XY: 73 AN XY: 135914

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000527

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000317 AC: 464 AN: 1461892 Hom.: 3 Cov.: 41 AF XY: 0.000391 AC XY: 284 AN XY: 727248

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74438

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000499 Hom.: 1

Bravo AF: 0.000280

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2021	This variant is associated with the following publications: (PMID: 28322503) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 387 of the ILDR1 protein (p.Ser387Pro). This variant is present in population databases (rs150250182, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ILDR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 178382). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 18, 2016

p.Ser387Pro in Exon 7 of ILDR1: This variant is not expected to have clinical si gnificance due to a lack of conservation across species with several mammals hav ing this variant (Pro) at this position. In addition, computational prediction t ools do not suggest a high likelihood of impact to the protein, and it has been across several populations with a highest frequency of 0.1% (19/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs150250182). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.3
DANN	Benign	0.87
DEOGEN2	Benign	0.0013	.;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.48	T;.;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0098	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.76	.;N;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.37	N;N;.;N
REVEL	Benign	0.027
Sift	Benign	0.30	T;T;.;T
Sift4G	Benign	0.32	T;T;.;T
Polyphen		0.0010	B;B;B;B
Vest4		0.10
MVP		0.60
MPC		0.046
ClinPred		0.0047	T
GERP RS		1.6
Varity_R		0.12
gMVP		0.11

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: rs150250182; hg19: chr3-121712437;