4-57110400-C-A

Variant names:

• chr4-57110400-C-A
• rs4074555
• ENST00000499667.6:n.209+430C>A

Variant summary

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

The ENST00000947223.1(IGFBP7):​c.-49G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,249,564 control chromosomes in the GnomAD database, including 9,567 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 0.15 (2500 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7067 hom.)
• Consequence: IGFBP7 ENST00000947223.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.96
• Publications: 5 publications found

Genes affected

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

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

ENSG00000287369 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000947223.1. 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-AS1	NR_034081.1		n.209+430C>A		intron	N/A
	IGFBP7	NM_001553.3	MANE Select	c.-49G>T		upstream_gene	N/A	NP_001544.1	Q16270-1
	IGFBP7	NM_001253835.2		c.-49G>T		upstream_gene	N/A	NP_001240764.1	Q16270-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGFBP7-AS1	ENST00000499667.6	TSL:1	n.209+430C>A		intron	N/A
	IGFBP7	ENST00000947223.1		c.-49G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000617282.1
	IGFBP7	ENST00000896421.1		c.-49G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000566480.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23200 AN: 151194 Hom.: 2501 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0865

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.137

Gnomad NFE AF: 0.0797

Gnomad OTH AF: 0.136

GnomAD2 exomes AF: 0.374 AC: 119 AN: 318 AF XY: 0.342

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.500

Gnomad EAS exome AF: 0.500

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.0956 AC: 105000 AN: 1098262 Hom.: 7067 Cov.: 31 AF XY: 0.0959 AC XY: 50335 AN XY: 524888

African (AFR) AF: 0.310 AC: 6919 AN: 22342

American (AMR) AF: 0.150 AC: 1182 AN: 7872

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 1384 AN: 13798

East Asian (EAS) AF: 0.392 AC: 9828 AN: 25060

South Asian (SAS) AF: 0.128 AC: 3643 AN: 28354

European-Finnish (FIN) AF: 0.0718 AC: 1634 AN: 22750

Middle Eastern (MID) AF: 0.122 AC: 350 AN: 2878

European-Non Finnish (NFE) AF: 0.0807 AC: 75143 AN: 931614

Other (OTH) AF: 0.113 AC: 4917 AN: 43594

GnomAD4 genome AF: 0.154 AC: 23226 AN: 151302 Hom.: 2500 Cov.: 32 AF XY: 0.154 AC XY: 11360 AN XY: 73942

African (AFR) AF: 0.287 AC: 11874 AN: 41406

American (AMR) AF: 0.136 AC: 2069 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.0865 AC: 299 AN: 3458

East Asian (EAS) AF: 0.347 AC: 1766 AN: 5084

South Asian (SAS) AF: 0.130 AC: 626 AN: 4824

European-Finnish (FIN) AF: 0.0707 AC: 729 AN: 10314

Middle Eastern (MID) AF: 0.140 AC: 41 AN: 292

European-Non Finnish (NFE) AF: 0.0797 AC: 5400 AN: 67730

Other (OTH) AF: 0.135 AC: 282 AN: 2096

Alfa AF: 0.0345 Hom.: 34

Bravo AF: 0.168

Asia WGS AF: 0.198 AC: 657 AN: 3324

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.38
DANN	Benign	0.86
PhyloP100		-6.0
PromoterAI		0.13	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4074555; hg19: chr4-57976566;