rs4619

Positions:

• chr7-45893070-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000596.4(IGFBP1):​c.759A>G​(p.Ile253Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,604,560 control chromosomes in the GnomAD database, including 105,432 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (11038 hom., cov: 32)
  • Exomes 𝑓: 0.36 (94394 hom.)
• Consequence: IGFBP1 NM_000596.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

Genes affected

IGFBP1 (HGNC:5469): (insulin like growth factor binding protein 1) This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP N-terminal domain and a thyroglobulin type-I domain. The encoded protein, mainly expressed in the liver, circulates in the plasma and binds both insulin-like growth factors (IGFs) I and II, prolonging their half-lives and altering their interaction with cell surface receptors. This protein is important in cell migration and metabolism. Low levels of this protein may be associated with impaired glucose tolerance, vascular disease and hypertension in human patients. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010901988).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP1	NM_000596.4	c.759A>G	p.Ile253Met	missense_variant	4/4	ENST00000275525.8	NP_000587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP1	ENST00000275525.8	c.759A>G	p.Ile253Met	missense_variant	4/4	1	NM_000596.4	ENSP00000275525.3
IGFBP1	ENST00000457280.5	c.753A>G	p.Ile251Met	missense_variant	4/4	5		ENSP00000413511.1
IGFBP1	ENST00000468955.1	c.630A>G	p.Ile210Met	missense_variant	3/3	5		ENSP00000417069.1

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57174 AN: 151910 Hom.: 11010 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.385

GnomAD3 exomes AF: 0.356 AC: 89401 AN: 251224 Hom.: 17018 AF XY: 0.345 AC XY: 46784 AN XY: 135792

Gnomad AFR exome AF: 0.459

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.553

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.355 AC: 515705 AN: 1452532 Hom.: 94394 Cov.: 29 AF XY: 0.349 AC XY: 252340 AN XY: 723078

Gnomad4 AFR exome AF: 0.456

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.320

Gnomad4 EAS exome AF: 0.482

Gnomad4 SAS exome AF: 0.207

Gnomad4 FIN exome AF: 0.337

Gnomad4 NFE exome AF: 0.360

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.377 AC: 57240 AN: 152028 Hom.: 11038 Cov.: 32 AF XY: 0.372 AC XY: 27651 AN XY: 74308

Gnomad4 AFR AF: 0.448

Gnomad4 AMR AF: 0.350

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.529

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.388

Alfa AF: 0.353 Hom.: 22404

Bravo AF: 0.391

TwinsUK AF: 0.381 AC: 1411

ALSPAC AF: 0.360 AC: 1388

ESP6500AA AF: 0.453 AC: 1998

ESP6500EA AF: 0.354 AC: 3041

ExAC AF: 0.355 AC: 43094

Asia WGS AF: 0.368 AC: 1280 AN: 3478

EpiCase AF: 0.349

EpiControl AF: 0.339

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.38
DEOGEN2	Benign	0.11	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.21	T;T;T
MetaRNN	Benign	0.0011	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.6	N;N;N
REVEL	Benign	0.074
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.020
MPC		0.35
ClinPred		0.0069	T
GERP RS		1.5
Varity_R		0.18
gMVP		0.49

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: rs4619; hg19: chr7-45932669; COSMIC: COSV51874191;