rs9282734

Positions:

• chr7-45917370-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000598.5(IGFBP3):​c.473A>C​(p.His158Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00922 in 1,614,050 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (318 hom.)
• Consequence: IGFBP3 NM_000598.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.311

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002375126).
• BP6: Variant 7-45917370-T-G is Benign according to our data. Variant chr7-45917370-T-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP3	NM_000598.5	c.473A>C	p.His158Pro	missense_variant	2/5	ENST00000613132.5	NP_000589.2
IGFBP3	NM_001013398.2	c.491A>C	p.His164Pro	missense_variant	2/5		NP_001013416.1
IGFBP3	XM_047420325.1	c.473A>C	p.His158Pro	missense_variant	2/4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5	c.473A>C	p.His158Pro	missense_variant	2/5	5	NM_000598.5	ENSP00000477772	P4

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2623 AN: 152078 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0127 AC: 3190 AN: 251466 Hom.: 67 AF XY: 0.0122 AC XY: 1660 AN XY: 135912

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.0652

Gnomad SAS exome AF: 0.0162

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00838 AC: 12247 AN: 1461854 Hom.: 318 Cov.: 31 AF XY: 0.00854 AC XY: 6211 AN XY: 727226

Gnomad4 AFR exome AF: 0.0389

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.00742

Gnomad4 EAS exome AF: 0.0920

Gnomad4 SAS exome AF: 0.0171

Gnomad4 FIN exome AF: 0.00260

Gnomad4 NFE exome AF: 0.00386

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0173 AC: 2634 AN: 152196 Hom.: 53 Cov.: 32 AF XY: 0.0175 AC XY: 1300 AN XY: 74408

Gnomad4 AFR AF: 0.0398

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.0750

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.00861 Hom.: 10

Bravo AF: 0.0192

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.0409 AC: 180

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.0134 AC: 1630

Asia WGS AF: 0.0530 AC: 183 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00403

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.66
DEOGEN2	Benign	0.022	T;T;T;.;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.50	T;T;T;T;T;T
MetaRNN	Benign	0.0024	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;.;M;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.3	N;.;N;N;.;N
REVEL	Benign	0.061
Sift	Benign	0.23	T;.;T;T;.;T
Sift4G	Benign	0.33	T;T;T;T;T;T
Polyphen		0.0040	B;.;B;.;.;.
Vest4		0.18
MPC		0.54
ClinPred		0.0054	T
GERP RS		1.8
Varity_R		0.13
gMVP		0.41

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: rs9282734; hg19: chr7-45956969; COSMIC: COSV51873150; COSMIC: COSV51873150;