chr7-45917365-C-G

Position:

• chr7-45917365-C-G

Variant summary

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

The NM_000598.5(IGFBP3):​c.478G>C​(p.Val160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IGFBP3 NM_000598.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.217

Genes affected

IGFBP3 (HGNC:5472): (insulin like growth factor binding protein 3) This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein forms a ternary complex with insulin-like growth factor acid-labile subunit (IGFALS) and either insulin-like growth factor (IGF) I or II. In this form, it circulates in the plasma, prolonging the half-life of IGFs and altering their interaction with cell surface receptors. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

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=0.05884111).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5	c.478G>C	p.Val160Leu	missense_variant	2/5	ENST00000613132.5	NP_000589.2
IGFBP3	NM_001013398.2	c.496G>C	p.Val166Leu	missense_variant	2/5		NP_001013416.1
IGFBP3	XM_047420325.1	c.478G>C	p.Val160Leu	missense_variant	2/4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5	c.478G>C	p.Val160Leu	missense_variant	2/5	5	NM_000598.5	ENSP00000477772.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.496G>C (p.V166L) alteration is located in exon 2 (coding exon 2) of the IGFBP3 gene. This alteration results from a G to C substitution at nucleotide position 496, causing the valine (V) at amino acid position 166 to be replaced by a leucine (L). 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	Benign	0.092
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.7
DANN	Benign	0.49
DEOGEN2	Benign	0.0055	T;T;T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.61	T;T;T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.059	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	.;.;L;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.63	N;.;N;N;.;N
REVEL	Benign	0.035
Sift	Benign	0.47	T;.;T;T;.;T
Sift4G	Benign	0.71	T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.
Vest4		0.15
MutPred		0.18		.;.;Gain of catalytic residue at V160 (P = 0.0578);.;.;.;
MVP		0.23
MPC		0.34
ClinPred		0.042	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs369707352; hg19: chr7-45956964;