4-57110117-C-T

Variant names:

• chr4-57110117-C-T
• rs1170311023
• NM_001553.3:c.235G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001553.3(IGFBP7):​c.235G>A​(p.Gly79Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGFBP7 NM_001553.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.859

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06759146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGFBP7	NM_001553.3	c.235G>A	p.Gly79Arg	missense_variant	Exon 1 of 5	ENST00000295666.6	NP_001544.1
IGFBP7	NM_001253835.2	c.235G>A	p.Gly79Arg	missense_variant	Exon 1 of 4		NP_001240764.1
IGFBP7-AS1	NR_034081.1	n.209+147C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP7	ENST00000295666.6	c.235G>A	p.Gly79Arg	missense_variant	Exon 1 of 5	1	NM_001553.3	ENSP00000295666.4
IGFBP7-AS1	ENST00000499667.6	n.209+147C>T		intron_variant	Intron 1 of 4	1
IGFBP7	ENST00000514062.2	c.235G>A	p.Gly79Arg	missense_variant	Exon 1 of 4	2		ENSP00000486293.1
IGFBP7-AS1	ENST00000508328.6	n.191+147C>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1362516 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 672528

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 Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.235G>A (p.G79R) alteration is located in exon 1 (coding exon 1) of the IGFBP7 gene. This alteration results from a G to A substitution at nucleotide position 235, causing the glycine (G) at amino acid position 79 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.011
Sift	Benign	0.54	T;.
Sift4G	Benign	0.51	T;T
Polyphen		0.046	B;.
Vest4		0.20
MutPred		0.35		Gain of MoRF binding (P = 0.0302);Gain of MoRF binding (P = 0.0302);
MVP		0.11
MPC		0.53
ClinPred		0.11	T
GERP RS		2.7
Varity_R		0.15
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs1170311023; hg19: chr4-57976283;