Genetic Variant IGFBP7:c.585+4T>A (chr4-57040820-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001553.3(IGFBP7):c.585+4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,592,102 control chromosomes in the GnomAD database, including 109,621 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9335 hom., cov: 33)

Exomes 𝑓: 0.37 ( 100286 hom. )

Consequence

IGFBP7
NM_001553.3 splice_region, intron

Scores

Splicing: ADA: 0.00004899

Clinical Significance

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

Conservation

PhyloP100: 0.323

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 4-57040820-A-T is Benign according to our data. Variant chr4-57040820-A-T is described in ClinVar as Benign. ClinVar VariationId is 1299709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

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.585+4T>A		splice_region intron	N/A	NP_001544.1	Q16270-1
	IGFBP7	NM_001253835.2		c.585+4T>A		splice_region intron	N/A	NP_001240764.1	Q16270-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IGFBP7	ENST00000295666.6	TSL:1 MANE Select	c.585+4T>A	splice_region intron	N/A	ENSP00000295666.4	Q16270-1
IGFBP7	ENST00000896424.1		c.693+4T>A	splice_region intron	N/A	ENSP00000566483.1
IGFBP7	ENST00000947223.1		c.660+4T>A	splice_region intron	N/A	ENSP00000617282.1

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52434

AN:

152040

Hom.:

9325

Cov.:

show subpopulations

Gnomad AFR

AF:

0.311

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.280

Gnomad ASJ

AF:

0.474

Gnomad EAS

AF:

0.217

Gnomad SAS

AF:

0.402

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.380

Gnomad OTH

AF:

0.351

GnomAD2 exomes

AF:

0.347

AC:

86887

AN:

250386

AF XY:

0.359

show subpopulations

Gnomad AFR exome

AF:

0.317

Gnomad AMR exome

AF:

0.227

Gnomad ASJ exome

AF:

0.476

Gnomad EAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.369

AC:

530628

AN:

1439946

Hom.:

100286

Cov.:

AF XY:

0.373

AC XY:

267692

AN XY:

717908

show subpopulations

African (AFR)

AF:

0.305

AC:

10085

AN:

33044

American (AMR)

AF:

0.233

AC:

10407

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.483

AC:

12571

AN:

26014

East Asian (EAS)

AF:

0.207

AC:

8186

AN:

39592

South Asian (SAS)

AF:

0.423

AC:

36255

AN:

85744

European-Finnish (FIN)

AF:

0.335

AC:

17869

AN:

53376

Middle Eastern (MID)

AF:

0.494

AC:

2790

AN:

5644

European-Non Finnish (NFE)

AF:

0.376

AC:

410291

AN:

1092200

Other (OTH)

AF:

0.372

AC:

22174

AN:

59674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

16397

32794

49191

65588

81985

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12736

25472

38208

50944

63680

<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:

0.345

AC:

52482

AN:

152156

Hom.:

9335

Cov.:

AF XY:

0.345

AC XY:

25634

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.311

AC:

12927

AN:

41514

American (AMR)

AF:

0.280

AC:

4285

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.474

AC:

1645

AN:

3472

East Asian (EAS)

AF:

0.217

AC:

1124

AN:

5170

South Asian (SAS)

AF:

0.402

AC:

1939

AN:

4818

European-Finnish (FIN)

AF:

0.334

AC:

3524

AN:

10566

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.380

AC:

25808

AN:

67996

Other (OTH)

AF:

0.351

AC:

743

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1763

3526

5290

7053

8816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.383

Hom.:

3760

Bravo

AF:

0.337

Asia WGS

AF:

0.292

AC:

1017

AN:

3478

EpiCase

AF:

0.392

EpiControl

AF:

0.397

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial retinal arterial macroaneurysm (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

(source)

DANN

Benign

0.54

PhyloP100

0.32

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000049

dbscSNV1_RF

Benign

0.012

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

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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