rs9282734

Variant names:

• chr7-45917370-T-G
• rs9282734
• NM_000598.5:c.473A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong 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. 14/21 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: 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
• Publications: 18 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.002375126).
• 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 rank	MANE	Protein	UniProt
IGFBP3	NM_000598.5	c.473A>C	p.His158Pro	missense_variant	Exon 2 of 5	ENST00000613132.5	NP_000589.2
IGFBP3	NM_001013398.2	c.491A>C	p.His164Pro	missense_variant	Exon 2 of 5		NP_001013416.1
IGFBP3	XM_047420325.1	c.473A>C	p.His158Pro	missense_variant	Exon 2 of 4		XP_047276281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGFBP3	ENST00000613132.5	c.473A>C	p.His158Pro	missense_variant	Exon 2 of 5	5	NM_000598.5	ENSP00000477772.2

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

GnomAD2 exomes AF: 0.0127 AC: 3190 AN: 251466 AF XY: 0.0122

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 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

African (AFR) AF: 0.0389 AC: 1302 AN: 33476

American (AMR) AF: 0.00541 AC: 242 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00742 AC: 194 AN: 26136

East Asian (EAS) AF: 0.0920 AC: 3654 AN: 39700

South Asian (SAS) AF: 0.0171 AC: 1473 AN: 86256

European-Finnish (FIN) AF: 0.00260 AC: 139 AN: 53420

Middle Eastern (MID) AF: 0.0150 AC: 86 AN: 5744

European-Non Finnish (NFE) AF: 0.00386 AC: 4289 AN: 1112008

Other (OTH) AF: 0.0144 AC: 868 AN: 60390

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

African (AFR) AF: 0.0398 AC: 1651 AN: 41530

American (AMR) AF: 0.0116 AC: 177 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.0750 AC: 387 AN: 5160

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4808

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00375 AC: 255 AN: 68014

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0102 Hom.: 77

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;.;.;.
PhyloP100		0.31
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
PromoterAI		-0.030	Neutral
Varity_R		0.13
gMVP		0.41
Mutation Taster		=91/9	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: rs9282734; hg19: chr7-45956969; COSMIC: COSV51873150; COSMIC: COSV51873150;