Genetic Variant IGFBP7:p.Pro187Pro (chr4-57040848-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_001553.3(IGFBP7):c.561G>A(p.Pro187Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,072 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 5 hom., cov: 33)

Exomes 𝑓: 0.011 ( 120 hom. )

Consequence

IGFBP7
NM_001553.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.105

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

familial retinal arterial macroaneurysm
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet

IGFBP7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 4-57040848-C-T is Benign according to our data. Variant chr4-57040848-C-T is described in ClinVar as Benign. ClinVar VariationId is 791477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.105 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001553.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP7	NM_001553.3	MANE Select	c.561G>A	p.Pro187Pro	synonymous	Exon 2 of 5	NP_001544.1	Q16270-1
	IGFBP7	NM_001253835.2		c.561G>A	p.Pro187Pro	synonymous	Exon 2 of 4	NP_001240764.1	Q16270-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IGFBP7	ENST00000295666.6	TSL:1 MANE Select	c.561G>A	p.Pro187Pro	synonymous	Exon 2 of 5	ENSP00000295666.4	Q16270-1
IGFBP7	ENST00000896424.1		c.669G>A	p.Pro223Pro	synonymous	Exon 4 of 7	ENSP00000566483.1
IGFBP7	ENST00000947223.1		c.636G>A	p.Pro212Pro	synonymous	Exon 3 of 6	ENSP00000617282.1

Frequencies

GnomAD3 genomes

AF:

0.00735

AC:

1118

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00857

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.00525

GnomAD2 exomes

AF:

0.00758

AC:

1904

AN:

251220

AF XY:

0.00768

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00983

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00993

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.0106

AC:

15459

AN:

1460754

Hom.:

120

Cov.:

AF XY:

0.0104

AC XY:

7533

AN XY:

726744

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33466

American (AMR)

AF:

0.00284

AC:

127

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00895

AC:

234

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00459

AC:

396

AN:

86208

European-Finnish (FIN)

AF:

0.0104

AC:

556

AN:

53414

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0122

AC:

13576

AN:

1111018

Other (OTH)

AF:

0.00830

AC:

501

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

719

1437

2156

2874

3593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

492

984

1476

1968

2460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00733

AC:

1117

AN:

152318

Hom.:

Cov.:

AF XY:

0.00729

AC XY:

543

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41564

American (AMR)

AF:

0.00438

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00395

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00857

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

840

AN:

68034

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.00672

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0108

EpiControl

AF:

0.0107

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

7.2

(source)

DANN

Benign

0.63

PhyloP100

-0.10

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over