4-57073697-T-G

Variant names:

• chr4-57073697-T-G
• rs10049992
• NM_001553.3:c.476-32764A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001553.3(IGFBP7):​c.476-32764A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 152,094 control chromosomes in the GnomAD database, including 2,391 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2391 hom., cov: 31)
• Consequence: IGFBP7 NM_001553.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.205
• Publications: 8 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP7	NM_001553.3	MANE Select	c.476-32764A>C		intron	N/A	NP_001544.1
	IGFBP7	NM_001253835.2		c.476-32764A>C		intron	N/A	NP_001240764.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP7	ENST00000295666.6	TSL:1 MANE Select	c.476-32764A>C		intron	N/A	ENSP00000295666.4
	IGFBP7	ENST00000896424.1		c.451-30620A>C		intron	N/A	ENSP00000566483.1
	IGFBP7	ENST00000947223.1		c.476-31775A>C		intron	N/A	ENSP00000617282.1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26264 AN: 151976 Hom.: 2388 Cov.: 31

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.167

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.173 AC: 26278 AN: 152094 Hom.: 2391 Cov.: 31 AF XY: 0.175 AC XY: 13036 AN XY: 74358

African (AFR) AF: 0.153 AC: 6371 AN: 41508

American (AMR) AF: 0.119 AC: 1819 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 622 AN: 3466

East Asian (EAS) AF: 0.305 AC: 1573 AN: 5158

South Asian (SAS) AF: 0.180 AC: 871 AN: 4826

European-Finnish (FIN) AF: 0.247 AC: 2614 AN: 10566

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11790 AN: 67976

Other (OTH) AF: 0.166 AC: 350 AN: 2106

Alfa AF: 0.169 Hom.: 3472

Bravo AF: 0.164

Asia WGS AF: 0.242 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	8.1
DANN	Benign	0.71
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10049992; hg19: chr4-57939863;