rs1009728

Positions:

• chr17-40452955-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The ENST00000269593.5(IGFBP4):​c.350-30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,450,950 control chromosomes in the GnomAD database, including 73,456 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.30 (7072 hom., cov: 31)
  • Exomes 𝑓: 0.31 (66384 hom.)
• Consequence: IGFBP4 ENST00000269593.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.974

Genes affected

IGFBP4 (HGNC:5473): (insulin like growth factor binding protein 4) 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 binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma in both glycosylated and non-glycosylated forms. Binding of this protein prolongs the half-life of the IGFs and alters their interaction with cell surface receptors. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGFBP4	NM_001552.3	c.350-30T>C		intron_variant		ENST00000269593.5	NP_001543.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGFBP4	ENST00000269593.5	c.350-30T>C		intron_variant		1	NM_001552.3	ENSP00000269593	P1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44853 AN: 151890 Hom.: 7061 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.361

GnomAD3 exomes AF: 0.325 AC: 53028 AN: 163000 Hom.: 9320 AF XY: 0.334 AC XY: 29398 AN XY: 88076

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.242

Gnomad ASJ exome AF: 0.419

Gnomad EAS exome AF: 0.520

Gnomad SAS exome AF: 0.425

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.314

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.314 AC: 407295 AN: 1298942 Hom.: 66384 Cov.: 30 AF XY: 0.318 AC XY: 201655 AN XY: 634964

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.258

Gnomad4 ASJ exome AF: 0.414

Gnomad4 EAS exome AF: 0.518

Gnomad4 SAS exome AF: 0.416

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.295 AC: 44894 AN: 152008 Hom.: 7072 Cov.: 31 AF XY: 0.298 AC XY: 22173 AN XY: 74288

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.528

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.366

Alfa AF: 0.311 Hom.: 4612

Bravo AF: 0.291

Asia WGS AF: 0.483 AC: 1679 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.55
BranchPoint Hunter		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1009728; hg19: chr17-38609207; COSMIC: COSV54096927;