Genetic Variant IGFLR1:p.Pro220Leu (chr19-35739772-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024660.4(IGFLR1):c.659C>T(p.Pro220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000447 in 1,565,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

IGFLR1
NM_024660.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.232

Publications

1 publications found

Variant links:

Genes affected

IGFLR1 (HGNC:23620): (IGF like family receptor 1) Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

IGFLR1 links:

ENSG00000267120 (HGNC:):

ENSG00000267120 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11589199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFLR1	NM_024660.4 link	c.659C>T	p.Pro220Leu	missense_variant	Exon 4 of 5	ENST00000246532.6	NP_078936.1	Q9H665-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGFLR1	ENST00000246532.6 link	c.659C>T	p.Pro220Leu	missense_variant	Exon 4 of 5	1	NM_024660.4	ENSP00000246532.1	Q9H665-1
ENSG00000267120	ENST00000589807.1 link	n.*1153C>T		non_coding_transcript_exon_variant	Exon 10 of 11	2		ENSP00000472696.1	M0R2N4
ENSG00000267120	ENST00000589807.1 link	n.*1153C>T		3_prime_UTR_variant	Exon 10 of 11	2		ENSP00000472696.1	M0R2N4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000425

AC:

AN:

1413286

Hom.:

Cov.:

AF XY:

0.00000575

AC XY:

AN XY:

696258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32484

American (AMR)

AF:

0.00

AC:

AN:

40968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22626

East Asian (EAS)

AF:

0.00

AC:

AN:

39186

South Asian (SAS)

AF:

0.00

AC:

AN:

78324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5534

European-Non Finnish (NFE)

AF:

0.00000553

AC:

AN:

1084544

Other (OTH)

AF:

0.00

AC:

AN:

58236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.659C>T (p.P220L) alteration is located in exon 4 (coding exon 3) of the IGFLR1 gene. This alteration results from a C to T substitution at nucleotide position 659, causing the proline (P) at amino acid position 220 to be replaced by a leucine (L). 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

0.095

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.062

T;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.52

.;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.49

MutationAssessor

Benign

2.0

M;M

PhyloP100

0.23

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-3.9

D;.

REVEL

Benign

0.12

Sift

Benign

0.17

T;.

Sift4G

Uncertain

0.010

D;D

Polyphen

0.11

B;B

Vest4

0.18

MutPred

0.12

Loss of relative solvent accessibility (P = 0.0071);Loss of relative solvent accessibility (P = 0.0071);

MVP

0.33

MPC

0.29

ClinPred

0.21

GERP RS

-0.062

Varity_R

0.083

gMVP

0.20

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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19-35739772-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over