rs4619

Variant names:

• chr7-45893070-A-G
• rs4619
• NM_000596.4:c.759A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 0.38 (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
• Publications: 60 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
IGFBP1	NM_000596.4	c.759A>G	p.Ile253Met	missense_variant	Exon 4 of 4	ENST00000275525.8	NP_000587.1

Ensembl

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

GnomAD2 exomes AF: 0.356 AC: 89401 AN: 251224 AF XY: 0.345

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 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

African (AFR) AF: 0.456 AC: 15144 AN: 33240

American (AMR) AF: 0.381 AC: 17024 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8340 AN: 26068

East Asian (EAS) AF: 0.482 AC: 19080 AN: 39626

South Asian (SAS) AF: 0.207 AC: 17844 AN: 86028

European-Finnish (FIN) AF: 0.337 AC: 17983 AN: 53322

Middle Eastern (MID) AF: 0.243 AC: 1378 AN: 5682

European-Non Finnish (NFE) AF: 0.360 AC: 397474 AN: 1103818

Other (OTH) AF: 0.357 AC: 21438 AN: 60076

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

African (AFR) AF: 0.448 AC: 18554 AN: 41454

American (AMR) AF: 0.350 AC: 5347 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1136 AN: 3468

East Asian (EAS) AF: 0.529 AC: 2730 AN: 5162

South Asian (SAS) AF: 0.208 AC: 1001 AN: 4818

European-Finnish (FIN) AF: 0.319 AC: 3361 AN: 10552

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23989 AN: 67976

Other (OTH) AF: 0.388 AC: 820 AN: 2112

Alfa AF: 0.361 Hom.: 47099

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;.;.
PhyloP100		1.1
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
Mutation Taster		=99/1	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: rs4619; hg19: chr7-45932669; COSMIC: COSV51874191;