Genetic Variant IGFBPL1:p.Arg216Gln (chr9-38413277-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001007563.3(IGFBPL1):c.647G>A(p.Arg216Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,614,014 control chromosomes in the GnomAD database, including 3 homozygotes. 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 (★).

Frequency

Genomes: 𝑓 0.00086 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

IGFBPL1
NM_001007563.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.440

Variant links:

Genes affected

IGFBPL1 (HGNC:20081): (insulin like growth factor binding protein like 1) Predicted to enable insulin-like growth factor binding activity. Involved in cellular response to tumor cell. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

IGFBPL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04973808).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBPL1	NM_001007563.3 link	c.647G>A	p.Arg216Gln	missense_variant	Exon 3 of 5	ENST00000377694.2	NP_001007564.1	Q8WX77

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBPL1	ENST00000377694.2 link	c.647G>A	p.Arg216Gln	missense_variant	Exon 3 of 5	2	NM_001007563.3	ENSP00000366923.1		Q8WX77

Frequencies

GnomAD3 genomes

AF:

0.000854

AC:

130

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000708

AC:

178

AN:

251252

Hom.:

AF XY:

0.000758

AC XY:

103

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000899

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00120

AC:

1753

AN:

1461692

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

844

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00146

Gnomad4 OTH exome

AF:

0.00128

GnomAD4 genome

AF:

0.000860

AC:

131

AN:

152322

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000978

Hom.:

Bravo

AF:

0.000827

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.647G>A (p.R216Q) alteration is located in exon 3 (coding exon 3) of the IGFBPL1 gene. This alteration results from a G to A substitution at nucleotide position 647, causing the arginine (R) at amino acid position 216 to be replaced by a glutamine (Q). 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

0.090

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.089

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.77

M_CAP

Benign

0.041

MetaRNN

Benign

0.050

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.40

Sift

Benign

0.037

Sift4G

Benign

0.11

Polyphen

0.73

Vest4

0.19

MVP

0.74

MPC

0.35

ClinPred

0.035

GERP RS

1.7

Varity_R

0.15

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over