Genetic Variant IGFBP7:p.Arg78Met (chr4-57110119-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001553.3(IGFBP7):c.233G>T(p.Arg78Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R78G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IGFBP7
NM_001553.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.323

Variant links:

Genes affected

IGFBP7 (HGNC:5476): (insulin like growth factor binding protein 7) This gene encodes a member of the insulin-like growth factor (IGF)-binding protein (IGFBP) family. IGFBPs bind IGFs with high affinity, and regulate IGF availability in body fluids and tissues and modulate IGF binding to its receptors. This protein binds IGF-I and IGF-II with relatively low affinity, and belongs to a subfamily of low-affinity IGFBPs. It also stimulates prostacyclin production and cell adhesion. Alternatively spliced transcript variants encoding different isoforms have been described for this gene, and one variant has been associated with retinal arterial macroaneurysm (PMID:21835307). [provided by RefSeq, Dec 2011]

IGFBP7 links:

IGFBP7-AS1 (HGNC:40296): (IGFBP7 antisense RNA 1)

IGFBP7-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21514195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP7	NM_001553.3 link	c.233G>T	p.Arg78Met	missense_variant	Exon 1 of 5	ENST00000295666.6	NP_001544.1	Q16270-1
IGFBP7	NM_001253835.2 link	c.233G>T	p.Arg78Met	missense_variant	Exon 1 of 4		NP_001240764.1	Q16270-2
IGFBP7-AS1	NR_034081.1 link	n.209+149C>A		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGFBP7	ENST00000295666.6 link	c.233G>T	p.Arg78Met	missense_variant	Exon 1 of 5	1	NM_001553.3	ENSP00000295666.4	Q16270-1
IGFBP7-AS1	ENST00000499667.6 link	n.209+149C>A		intron_variant	Intron 1 of 4	1
IGFBP7	ENST00000514062.2 link	c.233G>T	p.Arg78Met	missense_variant	Exon 1 of 4	2		ENSP00000486293.1	Q16270-2
IGFBP7-AS1	ENST00000508328.6 link	n.191+149C>A		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1360968

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

671630

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Benign

0.017

T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.38

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.058

Sift

Benign

0.063

T;.

Sift4G

Benign

0.094

T;T

Polyphen

1.0

D;.

Vest4

0.29

MutPred

0.31

Loss of methylation at R78 (P = 0.0126);Loss of methylation at R78 (P = 0.0126);

MVP

0.28

MPC

0.86

ClinPred

0.78

GERP RS

3.5

Varity_R

0.18

gMVP

0.47

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over